Molecular Generation

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16 papers in the last four weeks, up 220% on the four weeks before. 0.2% of all new papers.

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Latest papers 172

Oct 6, 2026cs.LG

Evolutionary One-Step Generators: Fast and Diverse Sampling for Discrete Design

Several discrete design tasks, such as molecular discovery, require diverse collections of useful candidates at low computational cost. High validity alone does not guarantee a useful candidate library: repeatedly generating the same valid structures leaves few distinct alternatives. Training for both feasibility and diversity is challenging because many relevant criteria can only be evaluated after hard decoding. To address this challenge, we propose EGO (Evolutionary Generators with One-step inference), a framework for training compact generators directly on discrete outputs. The method combines distribution matching with structural constraints and optional diversity or history-dependent rewards, using antithetic low-rank evolution strategies without requiring criterion-specific differentiable surrogates. Once trained, the generator produces the entire graph in a single neural-network evaluation. On molecular generation benchmarks, our compact generator achieves over

50\times

the valid-and-unique yield per estimated dense operation compared to recent one-step flow-map baselines while retaining high chemical validity. In scaffold completion, EGO achieves an observed

44.3\times

speedup over MoLeR in generation to SMILES and produces approximately

10\times

as many filter-passing proposals within matched time budgets for generation and screening. Beyond chemistry, EGO produces

1.54\times

as many distinct held-out elite architectures as relaxed gradient training on NAS-Bench-101. The low generation cost may enable real-time candidate generation across discrete design tasks, supporting interactive exploration of constrained design spaces and rapid construction of candidate sets for downstream evaluation.

Marcus Vukojevic, Erik Nielsen, Veronica Lachi +2

University of Trento, Italy · UiT The Arctic University of Norway, Tromsø, Norway

Constrained Generative Modeling Graph Generation Molecular Graph Generation One-Step Generative Modeling Molecular Generation

Oct 5, 2026cs.LG

Latent Flow Matching for Molecular Graph Generation

Modern graph generative models typically operate directly in the discrete graph space, explicitly generating node and edge variables, which can become costly as graphs grow. In this paper, we perform generation explicitly on latent representations of entire graphs obtained from a pretrained Variational Autoencoder with high reconstruction fidelity. The generated representations, obtained through flow matching, are then decoded only at the final step. Across molecular benchmarks of increasing size, our approach achieves strong validity and FCD while offering a favorable quality-efficiency trade-off compared with state-of-the-art explicit graph generative models. One of the main advantages of this formulation is that the graph representation only needs to be learned once, after which the same one can be reused across multiple generative objectives without retraining. We demonstrate generation guided by molecular properties and further introduce validity-aware generation though a classifier learned directly in latent space. All code will be made available upon acceptance.

Mathis Goupillon, Roman Bresson, Konstantinos Divriotis +1

Mohamed bin Zayed University of Artificial Intelligence

Flow Matching Molecular Graph Generation Molecular Generation Flow-Based Generative Modeling

Oct 5, 2026cs.AI

From Benchmark to Bench: Can Agents Survive Real-World Drug Discovery?

Agentic systems increasingly coordinate molecular-design tools, but it is unclear which layer of the stack limits outcomes on real projects. We developed MAGI, an open modular agent that authors objectives, launches and monitors optimization, interprets structure--activity relationships, and revises its strategy accordingly. MAGI generates molecules either directly through the LLM or by delegating to REINVENT 4, with scoring services interchangeable behind a common contract. We tested it across nine retrospective lead-optimization campaigns from three pharmaceutical companies, replayed under fixed temporal cutoffs. Both routes produced valid structures: LLM proposals stayed closer to local chemistry and reached comparable or higher primary activity in fewer operations, whereas REINVENT explored broader chemical space. Whether a campaign met its objective depended on the predictive models, not on the generation route: attainment followed model accuracy on the chemistry proposed, dropping once that chemistry moved outside the model's applicability domain. Separately, a blinded evaluation asked whether the MAGI's output could pass as expert work: chemists were not able to discriminate agentic proposals from held-out compounds, and judged the SAR reasoning broadly plausible yet incomplete. Together, these results position MAGI as a coordination layer pluggable into existing computational chemistry workflows. The ceiling on real projects, however, remains currently set by scorer applicability rather than by tool orchestration.

Pierre Llompart, Levent Guner, Helen Lai +2

AMD Silo AI, Stockholm, Sweden · Molecular AI, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK · Molecular AI, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden +1

AI Agents for Scientific Discovery LLM Agent Orchestration Molecular Generation Drug Discovery

Oct 5, 2026cs.AI

Bridging the Evidence-to-Execution Gap:A Reflective Agent for Multi-Objective Peptide Design

Large language models (LLMs) can reason over scientific literature to devise design strategies, yet fail to reliably implement them for biological sequences. While protein generative models learn sequence patterns, they lack the capacity to incorporate literature evidence for multi-step reflective reasoning, forming an evidence-to-execution gap between scientific reasoning and sequence manipulation. We present EASER (Evidence-Aware Sequence Engineering with Reflection), a reflective agent bridging reasoning and sequence generation via a learned property interface of offline-trained, fixed low-rank matrices. The agent steers a diffusion generator by combining these matrices, proposing intervention hypotheses (anchors, editable positions, control coefficients) grounded in retrieved evidence, sequence context and past results. A Probe-and-Steer mechanism validates interventions and allocates samples according to predicted property responses, with outcome reflection informing subsequent decisions. Evaluated on multi-objective antimicrobial peptide design (optimizing activity, non-hemolysis and non-toxicity), explicit hypothesis formulation delivers better multi-objective performance than direct action generation under identical decision conditions. Ablation studies verify the importance of evidence retrieval, episodic history, reflection and Probe-and-Steer. Over six repeated trials, EASER obtains the highest mean hypervolume and lowest mean IGD+ on screened candidates compared with competing baselines. Our work demonstrates how an executable property interface and iterative feedback link scientific reasoning to targeted peptide sequence generation.

Haosen Zhang, Yang Yang

School of Agriculture and Biology, Shanghai Jiao Tong University · School of Computer Science, Shanghai Jiao Tong University

AI Agents for Scientific Discovery Large Language Model-Guided Optimization Molecular Generation Protein Design Multi-Objective Optimization

Oct 5, 2026cs.AI

DiMOS: Doob-Guided Inference-Time Multi-Objective Search for Scientific Design

Scientific design often requires jointly satisfying multiple objectives and constraints. Pretrained masked diffusion models provide a generative foundation for this task, but fine-tuning them to meet these objectives and constraints incurs additional training costs, motivating inference-time guidance with frozen models. However, such guidance faces two challenges: pass-or-fail constraints and black-box reward models may provide no useful gradients, while jointly satisfying multiple requirements can leave a small feasible region, making feasible designs difficult to find within a limited inference budget. To address these challenges, we introduce DiMOS, a training-free framework for multi-objective scientific design. Using joint rewards from candidate completions, DiMOS performs approximate Doob-guided local resampling without requiring reward gradients. To allocate computation efficiently, it uses budget-efficient trajectory search to focus computation on promising continuations. Across six DNA, protein, and RNA tasks, DiMOS attains the highest joint success rate at comparable generation times, up to

1.98\times

the strongest baseline on DNA and protein, while maintaining high sequence uniqueness and naturalness.

Ziqing Wang, Qijie Zhu, Weimin Wu +4

Northwestern University

Masked Diffusion Models Inference-Time Search Molecular Generation Multi-Objective Optimization Inference-Time Guidance

Oct 1, 2026cs.LG

Higher-Order Molecular Grammars for Generative and Foundation Models in Chemistry

Molecular learning models are strongly shaped by their underlying representations. Yet standard sequential and graph formalisms struggle to explicitly encode higher-order topology, such as ring systems and recurring motifs. Existing higher-order representations can capture these structures directly, but they are often computationally demanding and difficult to decode into valid molecules. Here, we introduce Higher-order Grammar Representation (HGR), a principled, topology-aware framework that lifts molecules to combinatorial complexes and parses each complex into a compact sequence of production rules under a context-free higher-order grammar. By serialising higher-order topology into rule sequences, HGR makes these structures directly compatible with standard sequence models, avoiding the computational overhead of explicit higher-order encodings while preserving topological expressiveness. To reduce benchmark bias towards simple ring systems, we construct RingDiv, a ring-enriched benchmark containing 1.18 million molecules, including the curated RingDiv300k subset, and introduce the ring diversity index (RDI) to quantify ring-system coverage. In molecular generation, HGR-based models uniquely combine 100% validity by construction with leading distributional alignment, ranking first in FCD on all five generation benchmarks. In representation learning, HGR-FM achieves the highest mean AUC across seven MoleculeNet benchmarks under both transfer protocols, improving on the strongest baseline by 8.3 and 3.3 AUC points under probing and full fine-tuning, respectively. Collectively, these results establish HGR as an efficient higher-order representation for molecular generation and transferable representation learning.

Yiming Huang, Yujie Zeng, Vijay Prakash Dwivedi +4

Department of Computing, Imperial College London, London, UK · School of Electronic Engineering and Computer Science, Queen Mary University of London, London, UK · Department of Computer Science, Stanford University, Stanford, CA, USA +1

Graph Representation Learning Molecular Generation Topological Representation Learning Molecular Representation Learning

Oct 1, 2026cs.CE

CODesign: Consistency from Data to Trajectory in All-Atom Protein Binder Co-Design

The central challenge in de novo protein design is generating plausible, mutually compatible structures and sequences, such that each designed sequence folds into its intended structure and the structure accommodates that sequence. Compared to typical two-stage design methods, which decouple the modeling of the interdependent modalities, co-design models improve the cross-modal consistency by jointly generating sequences and structures. However, naively generating sequences and structures simultaneously does not ensure their consistency. To address this challenge, we propose CODesign framework. We improve data consistency by generating approximately 105,000 consistency-distilled dimers. We further promote consistency through a multimodal joint flow model that captures the joint distribution of sequences, backbone structures, and local atomic configurations, together with a consistency-aware joint resampling strategy that iteratively refines sequences and side chains. Experiments show that CODesign achieves state-of-the-art performance with the highest in silico success rates on both protein- and ligand-target binder design. Ablation studies also demonstrate our distilled dataset increases performance by 70.9%, which can be further improved by our proposed resampling mechanism with negligible additional computational cost. Code, model weights and the new dataset will be completely open-source.

Yuanle Mo, Bo Qiang, Haitao Lin +4

Valhalla Technology · The Chinese University of Hong Kong · University of Washington +2

Molecular Generation Protein Design Protein Binder Design

Sep 30, 2026cs.LG

Grand Canonical Generators

We introduce Grand Canonical Generators (GCG), a generative framework that extends Boltzmann generators to the grand canonical ensemble. We present two designs. The first conditions a variable-size generative model on the chemical potential, sampling particle number and configuration jointly. The second factorizes the grand canonical distribution into a particle-number distribution and the corresponding canonical Boltzmann density. This factorized formulation can use any existing Boltzmann generator for the canonical component, encodes the known linear chemical-potential dependence analytically, and yields a tractable likelihood that supports self-normalized importance sampling (SNIS). Empirically, GCG accurately reproduces grand canonical observables on a Lennard--Jones fluid and methane adsorption in a zeolite, demonstrating generalization across chemical potentials and correction via SNIS and grand canonical Monte Carlo.

Andreas Burger, Malte Franke, Luka Mucko +2

University of Toronto NVIDIA Vector Institute Toronto, Canada · ETH Zurich NCCR Catalysis Zurich, Switzerland · University of Toronto NVIDIA Vector Institute Acceleration Consortium CIFAR Toronto, Canada

Generative Modeling Molecular Generation Conditional Generative Modeling

Sep 30, 2026cs.LG

Analysis of Quantized and Efficiently Adapted Protein Language Models

Background: Protein language models (PLMs) are increasingly used for sequence generation and property prediction, but their size makes fine-tuning and deployment expensive. The effects of quantization and parameter efficient fine-tuning on performance, representations and generation remain insufficiently characterized. Results: We evaluated 4-bit quantization and low-rank adapter fine-tuning (QLoRA) across ESM-2, ESMC, ProtBERT, ProtT5, Ankh, Ankh3 and Profluent-E1. Across protein prediction tasks, many model-task pairs retained more than 90% of full fine-tuning performance. Peak GPU memory savings approached 90% for the largest models, although performance and efficiency varied by model, dataset and training configuration. QLoRA often preserved early-layer representations while inducing task-specific adaptations in middle and late layers, resembling full fine-tuning with smaller representational changes. Training speed and power effects were more varied. For unconditional generation with ProLLaMA, ProtGPT2, ProGen2, ProteinGLM and ESM3, 4-bit quantization largely preserved predicted structural and sequence-level properties, but token-level analysis revealed model-dependent shifts in autoregressive output distributions. Conclusion: QLoRA and 4-bit quantization reduce PLM computational requirements, particularly GPU memory usage. Our results support QLoRA as a first-pass strategy for memory limited adaptation, reserving full fine-tuning for challenging tasks, unstable architectures or low validation recovery. For generative PLMs, sequence-level and structural metrics should be complemented with distributional analysis, since downstream predictions alone may miss quantization-induced shifts. These approaches can broaden access to large-scale protein modelling while requiring model- and task-specific validation.

Ilan Yaniv Zeisler, Sebastian Clancy, Pouriya Bayat +8

Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada. · Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada. · Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. +2

Protein Language Models Quantization-Aware LoRA Molecular Generation Parameter-Efficient Fine-Tuning

Sep 29, 2026cs.LG

RetroGEF: Dynamic Graph Edit Flow for Single-Step Retrosynthesis

Retrosynthesis enables the discovery of viable synthetic routes to target molecules. It plays a central role in modern drug discovery and materials design. Retrosynthesis involves molecular graph transformations that can change both connectivity and graph size. These transformations may introduce reactant components absent from the target while revising the product-derived structure. To model these transformations, we propose RetroGEF, a flow-based generative model for single-step retrosynthesis. Starting from the target molecule, it constructs possible reactants by adding atoms and changing bonds in the molecular graph. RetroGEF models molecular transformations and changes in graph size within the same generative process, rather than relying on a fixed-size graph canvas. It learns this process directly from product--reactant pairs without requiring a prescribed edit order. Experiments on representative retrosynthesis benchmarks demonstrate that RetroGEF achieves state-of-the-art performance.

Xiaozhuang Song, Xuemin Chen, Xinjian Zhao +2

The Chinese University of Hong Kong, Shenzhen · Shanghai AI Laboratory

One-Step Generative Modeling Molecular Generation

Sep 28, 2026cs.AI

AbGaze: Attentive Geometric Representation Learning for End-to-End Antibody Design

Computational antibody design requires representations that capture the geometric patterns underlying antigen--antibody interactions, yet existing approaches often rely on scalar distances or surface-intrinsic features, leaving cross-molecular geometry largely implicit. We present AbGaze, an end-to-end antibody design framework based on attentive geometric representation learning, which encodes distance, spatial direction, and surface-normal orientation of antigen surfaces relative to antibody-residue local frames, and adaptively aggregates these geometric interactions according to their interfacial context. The learned interaction representation is shared across multi-CDR co-design, complex structure prediction, and affinity optimization, with local-frame geometric supervision further constraining the representation. AbGaze outperforms prior methods across all three tasks: relative to the second-best method, it improves amino-acid recovery by 7.1% and reduces structural error by 14.9% on average over the six CDRs, improves interface docking quality (DockQ) by 6.6%, and raises the affinity improvement rate (IMP) by 32.5%.

Jiashuo Wang, Siqi Fan, Yizhen Luo +1

Institute for AI Industry Research (AIR), Tsinghua University · Department of Computer Science and Technology, Tsinghua University · PharMolix Inc.

Geometric Representation Learning Molecular Generation Protein Design

Sep 28, 2026cs.LG

Learning to Re-Draft: A Variational Stackelberg Game for Discrete Diffusion

Discrete diffusion models offer the ability to re-draft, revisiting and correcting earlier tokens throughout generation. This capability depends on the forward corruption process that defines what the denoiser learns to correct. Masked diffusion models fix tokens once they are unmasked, while uniform diffusion permits revisions but relies on uniformly random token substitutions. We instead learn which substitutions are most useful for training the denoiser to re-draft. We introduce Variational Stackelberg Discrete Diffusion (VSDD), a framework for learning a semantically aware corruption process. VSDD formulates training as a leader-follower game: the leader defines a Markovian corruption process parameterized by the denoiser's token embeddings, while the follower optimizes a variational denoising objective with the corruption process held fixed. The leader rewards corruptions based on how much the denoiser improves after learning from them, rather than on how easily the current denoiser can reconstruct them. We measure this improvement under a fixed reference corruption process, approximate the follower's response with a one-step gradient update, and optimize the leader using a score-function estimator. We evaluate VSDD across molecular, text, and playlist generation. VSDD substantially improves molecular validity over uniform and masked diffusion, reduces text perplexity relative to uniform diffusion while remaining competitive with masked diffusion, and achieves sizable improvements in offline playlist recommendation metrics.

Dmitrii Moor, Federico Tomasi, Paul N. Bennett +2

Spotify, London, UK · Spotify, Boston, USA · Spotify, New York, USA

Bilevel Optimization Molecular Generation Diffusion Language Models Diffusion Models

Sep 28, 2026q-bio.BM

Continuous Variational Synthesis

Biological machine learning was long bottlenecked by the ability to synthesize designed DNA. Variational synthesis models control chemical reactions to physically manufacture quadrillions of designed sequences in DNA. However, training these generative models is challenging: constraints on chemical synthesis can force many parameters into a discrete space, limiting the ability to pre-train and fine-tune. In this article we train ``free'' variational synthesis models using stochastic gradient descent in continuous space, and then discretize with post-training quantization to impose hardware and wetware constraints. This enables variational synthesis models to satisfy stringent reward criteria, while still synthesizing diverse designs, achieving a strictly dominating quality-diversity Pareto frontier. We demonstrate by training variational synthesis models of enzymes, peptides, antibody CDRH3s, and regulatory DNA elements. In silico performance is maintained in vitro.

Alan N. Amin, Mattia G. Gollub, Andrei Slabodkin +2

JURA Bio, Inc. Boston, MA 02125, USA

Variational Autoencoders Constrained Generative Modeling Molecular Generation Protein Design

Sep 28, 2026cs.LG

One Sequence, Many Decodings: CAGenMol-2 Recasts Drug Design as Masked Molecular Inference

Drug design couples property evaluation, conditional generation, structure-based design, and local optimization, yet machine learning systems typically address these capabilities with separate task-specific models. We introduce CAGenMol-2, a masked diffusion molecular language model that represents molecules, continuous scalar properties, and 3D protein pockets within a single wrapped sequence. Within this pretrained interface, downstream operations are selected by which sequence regions are observed or masked at inference, allowing one checkpoint to perform property prediction, property- and pocket-conditioned generation, and partial-constraint design without task-specific architectures or backbone fine-tuning. We further propose Adaptive Fragment Optimization (AdaFO), a gradient-free mask-and-refill search that turns the masked decoder into an iterative local molecular optimizer. On CrossDocked2020, AdaFO increases Success Rate from 30.2% to 70.8%, the best reported under this protocol, while largely preserving drug-likeness and diversity. Finally, scaffold-preserving directional editing and CRBN/VHL case studies demonstrate its use in compound design workflows spanning local molecular editing, structure-based prioritization, and downstream simulation-based screening.

Yanting Li, Enyan Dai, Lei Wang +2

The Hong Kong University of Science and Technology (Guangzhou) · Jinan University, Guangzhou

Molecular Optimization Masked Diffusion Models Structure-Based Drug Design Molecular Generation Molecular Property Prediction

Sep 23, 2026cs.AI

MolDesignBench: Evaluating LLM-based Agent for Scenario-grounded Molecular Design

Real-world molecular design remains challenging for large language model (LLM)-based agents. It requires them to interpret design contexts, satisfy multiple constraints, identify infeasible specifications, and reason over multi-step tool outputs. Existing benchmarks do not capture this complexity, focusing instead on explicit and narrow constraints, only feasible problems, and single-path solutions. To address this gap, we propose MolDesignBench, a scenario-grounded benchmark that more closely reflects real-world molecular design for evaluating tool-augmented LLM agents. MolDesignBench comprises 2K generation and optimization instances that combine implicit requirements embedded in design narratives with explicit property and functional-group constraints, including infeasible cases, and require the effective use of 17 specialized chemistry tools. Experiments across diverse frontier LLMs reveal low success rates--with the best achieving only

\sim43

%--and frequent failures in implicit-constraint reasoning, infeasibility detection, and tool reasoning. The corresponding fine-grained failure-mode analysis identifies implicit constraint interpretation and infeasibility detection as the primary bottlenecks, establishing MolDesignBench as a rigorous testbed to guide future research on chemical agents. The benchmark, tool interface, and evaluation code are publicly available.

Yongjun Jeong, Hanbum Ko, Ye Rin Kim +6

Department of Artificial Intelligence, Korea University · LG AI Research · Department of Statistics, Korea University

Molecular Optimization LLM Agent Evaluation AI Agent Benchmarks Molecular Generation

Sep 17, 2026cs.AI

TorchCraft: Unified binder design by inverting an all-atom structure predictor

All-atom structure predictors model diverse molecular interactions, but using their learned structural priors for binder design remains challenging. Here we present TorchCraft, a unified binder-design framework that optimizes sequence logits through a frozen all-atom predictor. Implemented in TorchFold, TorchCraft combines confidence, contact, geometric, and sequence-prior objectives within a shared optimization procedure for minibinders, framework-conditioned VHHs, cyclic peptides, and ligand-binding proteins. Using pretrained AlphaFold 3 weights, TorchCraft generated representative minibinders and VHHs with experimentally measured binding across four targets in each format, without post hoc sequence redesign. Computational benchmarks further demonstrated the framework's applicability to cyclic peptides and ligand-conditioned pocket design. TorchCraft extends predictor inversion to multiple binder formats and molecular contexts, providing a common framework for reusing all-atom structural priors in design.

TorchCraft Team, Yu Liu, Zhouhanyu Shen +8

Changping Laboratory, Beijing, China

Molecular Generation Protein Design Protein Binder Design

Sep 14, 2026cs.LG

Ensemble-Conditioned Molecular Design

Molecular design is typically approached as a problem of finding molecules which can adopt a single bioactive conformation. In reality, molecules occupy a distribution over conformations, and many of the properties which determine whether a candidate is viable depend on that distribution rather than on any single conformer. We reframe molecular design as an optimisation of both the modes and properties of molecules' conformational ensembles, where modes can be represented as shapes, pharmacophore profiles or protein pockets, and properties are aggregate scalars computed over the whole distribution. To realise this we introduce ensemble-conditioned guidance, a framework which conditions 3D molecular generative models on both axes simultaneously. Mode conditions are composed adaptively at inference by combining the vector fields produced under each condition. Conditions may be targeted or avoided, mixed across modalities and combined in arbitrary numbers, allowing a wide range of design tasks to be expressed with a single trained model. We introduce adaptive symmetry learning to allow conditions from different reference frames to be composed, and extend our generative framework to enable flexible-size generation. We evaluate on new benchmarks for multi-mode conditioning and ensemble property optimisation, and apply the framework to two practical drug discovery tasks, dual-target binder design and active-state-selective agonist design, where in both cases conditioning on the additional state improves the desired outcome over single-state conditioning.

Ross Irwin, Alessandro Tibo, Jon Paul Janet +1

Molecular AI Discovery Sciences, R&D AstraZeneca Gothenburg, Sweden · Department of Computer Science and Engineering Chalmers University of Technology and University of Gothenburg Gothenburg, Sweden

Molecular Optimization Structure-Based Drug Design 3D Molecular Generation Molecular Generation Conditional Generative Modeling

Sep 9, 2026cs.LG

A Systematic Evaluation of Molecule Generation Models for De Novo Drug Design: From Benchmarks to Practical Insights

Molecule generation has emerged as a powerful computational tool for de novo drug design, enabling the exploration of chemical space beyond the limits of conventional virtual screening. The field has progressed rapidly, driven by advances in molecular representations, generative architectures, and target-aware modeling strategies. However, existing reviews typically address specific model families or application scenarios in isolation, rather than offering an integrated perspective on how these components collectively form a coherent generation workflow. In this review, we present a comprehensive evaluation of molecule generation models for de novo drug design, covering 82 methods across five deep generative frameworks, including recurrent neural network (RNN)- and Transformer-based models, variational autoencoders (VAEs), generative adversarial networks (GANs), flow-based models, and diffusion models. We first summarize widely used benchmarks and molecular representations, and then examine the methodological principles underlying both general and pocket-conditioned generation. A central contribution of this work is a systematic synthesis and comparative analysis of reported performance across commonly used benchmarks and evaluation metrics. We also summarize representative experimentally validated case studies. Looking ahead, we discuss future directions in standardized 3D data, interaction-aware generation, receptor flexibility, and multi-objective molecular design, with the aim of improving the reliability and experimental relevance of molecule generation. All collected benchmark resources, evaluation metrics, and model references are provided in a publicly accessible repository at https://github.com/JacklinGroup/molecule-generation-review.

Xinrui Xu, Xueer Wang, Dan Luo +2

School of Computer Science, Xiangtan University, Xiangtan 411105, China · College of Computer Science and Electronic Engineering, Hunan University, Changsha 410082, China · School of Chinese Medicine, Hong Kong Baptist University, 15 Baptist University Road, Kowloon Tong 999077, Kowloon, Hong Kong SAR, China

Structure-Based Drug Design Molecular Generation Generative AI Evaluation Drug Discovery

Sep 8, 2026stat.ML

Mode Coverage in Normalizing Flow Boltzmann Generators via Log-Ratio Variation

Normalizing flow Boltzmann generators retain a tractable pushforward density, but training with forward KL depends on target samples that may be biased or omit modes. As a result, a flow can miss target mass while its observed importance weights give a high effective sample size. We introduce the log-ratio variation

\X_ω

, the mean absolute pairwise difference of the target-to-pushforward log-density ratio under a weighting measure

ω

, and use it to define KLXX, a new loss function. Two log-ratio variations are added to the forward KL (denoted by the two X's): one weighted by the target to improve accuracy, the other by a mixture of quench and temper samples with pushforward samples to search candidate modes. We derive the Fisher--Rao gradient flow of KLXX, where both variations contribute nonpositive dissipation, and a fixed-surrogate error bound for KLXX. We use KLXX in an adaptive-staging Boltzmann generator, with importance reweighting at every stage. We bound the sampling error of its inference scheme when the stage weights are essentially bounded, and prove it asymptotically unbiased in the sample size. In the numerical tests, KLXX improves mode coverage over forward KL. It also improves the generator's per-stage diagnostics against the loss that built the schedule. The observables the generator recovers are close to independent references. The log-ratio variations thus supply information that the forward KL loss usually omits.

Qi Feng, Rongjie Lai, Di Qi +1

Department of Mathematics, Florida State University, Tallahassee, FL 32306 · Department of Mathematics, Purdue University, West Lafayette, IN 47907

Normalizing Flows Molecular Generation Flow-Based Generative Modeling Mode Collapse

Sep 8, 2026physics.chem-ph

Fixed-Dimensional Latent Flow for Generating Variable-Size 3D Molecules

Molecular size is coupled to composition, structure, and function, yet most 3D molecular generators require a predefined atom count. We introduce Equivariant-Free Transformer-Autoencoded Latent Flow Matching, a two-stage framework that samples a fixed-dimensional latent vector using flow matching and uses an autoregressive Transformer to determine molecular size, atom types, coordinates, and chemical attributes. Canonical atom ordering and rigid-pose alignment enable Transformers without equivariant layers, while decoded attributes guide bond reconstruction. On PCQM4Mv2, unconditional generation yields 87.9% unique, novel molecules passing sanitization and PoseBusters checks, exceeding baselines with lower end-to-end training and sampling time and higher end-to-end throughput. Across ten target HOMO-LUMO gaps, internal ranking retains 30% of screened candidates and increases the density functional theory-verified hit rate within 0.1 eV from 25.0% to 52.4%, while largely preserving novelty and diversity. These results demonstrate fixed-dimensional latent generation with autoregressive decoding as a practical approach to molecular design without prespecifying size.

Weichi Yao, Cameron Gruich, Bryan R. Goldsmith +1

Michigan Institute for Data & AI in Society University of Michigan, Ann Arbor, USA · Department of Chemical Engineering University of Michigan, Ann Arbor, USA · Department of Statistics University of Michigan, Ann Arbor, USA

3D Molecular Generation Molecular Generation Flow-Based Generative Modeling

Sep 8, 2026q-bio.BM

PocketVE: Stable and Property-Guided Structure-Based Drug Design with Variance-Exploding Diffusion

Protein-conditioned 3D molecule generation is a central challenge in structure-based drug design, requiring a balance between pocket compatibility, molecular properties, and physical geometry. We propose \textbf{PocketVE}, a protein-pocket-conditioned variance-exploding (VE) diffusion framework that couples stable coordinate denoising with inference-time property guidance. Specifically, PocketVE combines an EDM-style training and sampling setup for 3D denoising, classifier-free guidance for multi-property steering, and adaptive protein perturbation as a training-time pocket regularizer.On the CrossDocked2020 benchmark under GenBench3D, PocketVE improves Valid

_{3\text{D}}

from 58.6 to 80.6 and reduces strain energy from 457.4 to 127.9 relative to its guided TAGMol architectural parent; relative to TargetDiff, it attains comparable Valid

_{3\text{D}}

with lower strain energy (127.9 vs.\ 306.0), while retaining competitive docking and molecular-property scores under moderate guidance. A guidance-scale study shows that moderate guidance gives a favorable balance between target-related objectives and geometric quality, whereas stronger guidance can degrade geometry and distributional fidelity. Pocket-permutation and PoseCheck diagnostics further support pocket-specific spatial compatibility with reduced steric conflicts. Overall, the results suggest that geometric stability and inference-time property guidance should be considered as coupled design objectives.

Peining Zhang, Jinbo Bi

University of Connecticut Storrs, Connecticut 06269, USA

Diffusion Model Guidance Structure-Based Drug Design 3D Molecular Generation Molecular Generation 3D Diffusion Models

Sep 3, 2026cs.LG

SimpleDesign: A Joint Model for Protein Sequence and Structure Codesign

Proteins are fundamental to biological processes, with their function determined by the complex interplay between the amino acid sequence and the three-dimensional structure. Developing generative models capable of understanding this intrinsically multi-modal relationship is crucial for fields like drug discovery and protein engineering. Existing models often rely on a multi-stage training process where autoencoders that tokenize data into latent representations are trained in a first stage. Secondly, a generative model is trained on the latent representation of the autoencoder(s), i.e., generative modeling in a latent space. We hypothesize that this multi-stage training is not necessary to obtain performant co-design models and thus present SimpleDesign, an effective multi-modal protein design model trained directly in the data space. SimpleDesign leverages a single-stage end-to-end objective that combines discrete cross-entropy for sequences and a regression objective for structures. In order to effectively model the difference in sequence and structure modalities, we develop a Mixture-of-Transformer architecture that allows modality-specific processing while keeping global self-attention over both modalities. We train SimpleDesign on over 2M sequence-structure pairs achieving strong performance across co-design and unconditional sequence/structure generation benchmarks.

Jiarui Lu, Yuyang Wang, Yizhe Zhang +4

Mila, Université de Montréal, Apple · Apple

Unified Multimodal Models Generative Modeling Multimodal Generation Molecular Generation Protein Design

Sep 2, 2026physics.chem-ph

HiPoly: a hierarchical polymer-native AI framework for property prediction and generative design

Polymeric materials are central to modern technologies, with applications ranging from energy to health and transportation. Although AI has made significant advances in materials discovery, the hierarchical structure of polymers across multiple length scales makes them inherently difficult to represent in a unified and physically meaningful way. Here we introduce HiPoly, a polymer-native AI framework that processes complete polymer descriptions through a three-level hierarchical graph architecture built on the G2RINS representation. HiPoly encodes stochastic inter-monomer connectivity, composition, and molecular weight directly within its architecture, using physically motivated design principles that mirror the multi-scale nature of polymeric systems. The framework establishes an end-to-end AI-driven workflow from experimental formulation data to property prediction, generative molecular design, and physics-based validation through molecular simulations, all unified by a single polymer representation. We demonstrate state-of-the-art prediction accuracy for thermophysical properties of multi-component polymer systems, with ablation studies confirming that each hierarchical design choice contributes independently to model performance. As an example, the generative design pathway is applied here to the discovery of sustainable alternatives to persistent fluorinated polymers, where it is possible to identify and independently validate PFAS-free candidates with target surface-energy properties. This work demonstrates how polymer-native AI can accelerate discovery by linking representation, prediction, and design across complex polymer chemistries.

Ge Sun, Gervasio Zaldivar, Yuan Tian +5

Department of Chemical and Biomolecular Engineering, Tandon School of Engineering, New York University, Brooklyn, NY, USA · Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA · Department of Computer Science, Courant Institute of Mathematical Sciences, New York University, New York, NY, USA +3

Materials Property Prediction Materials Science Molecular Generation Graph Neural Networks

Sep 2, 2026stat.ML

Schrödinger Bridges on Lie Group Manifolds for Probabilistic Intrinsic Generation

Generative modeling directly on geometric manifolds can avoid errors introduced by flattening non-Euclidean data, repeated ambient projection, and coordinate inconsistency in Euclidean representations. Schrodinger bridges provide a probabilistic generative framework for entropy-regularized transport between prescribed endpoint distributions. We study Schrodinger bridges for kinetic dynamics on Lie group manifolds with state X_t = (g_t, xi_t) in G x g, allowing endpoint observations to constrain only the variables that are actually measured. In particular, the entropy projection determines the conditional law of the unobserved endpoint velocities. For the same observed endpoint bridge, we develop two computational realizations: Wrapped-Kernel Bridge Calibration (WKBC) uses an explicit periodized kinetic kernel on compact Abelian groups, whereas Reciprocal Conditional-Control Bridge Matching (RCCBM) handles compact non-Abelian groups through two-sided endpoint calibration and mollified conditional-control matching. The canonical teacher-mixture path law is itself a Markov reciprocal law, so forward generation uses a calibrated initial law and one learned Doob controller. Moreover, we establish a modular error bound in the bounded-Lipschitz path metric that provides a clean separation of errors due to endpoints, control regression, initialization, discretization, and related approximations. Experiments on multiple Lie group manifold datasets validate the feasibility and consistency of our proposed method, covering protein and RNA torsions, SO(3), U(n), and the Protein Conformational Transition Pathway Generation task using mdCATH trajectories in a compact reduced representation. The source code is publicly available at https://github.com/cafferyzhang12/Schr-dinger_Bridge_on_LieGroup.

Shizhe Zhang, Mingyang Zhao, Lei Ma

1National Biomedical Imaging Center, College of Future Technology, Peking University, Beijing, China · 2State Key Laboratory of Mathematical Sciences, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, China

Schrödinger Bridges Generative Modeling Lie Group Methods Molecular Generation

Aug 31, 2026cs.LG

Elite-Weighted Supervised Fine-tuning for Goal-Directed Molecular Optimization

Goal-directed optimization is essential for steering molecular generators to propose candidates with desired properties. However, it is often implemented with policy-gradient reinforcement learning, which requires a generation-trajectory log-probability whose form depends on the model architecture and generation procedure. This makes an optimizer difficult to reuse across architectures and conditional generative designs. Supervised fine-tuning needs none of that machinery, but its update is driven by a fixed dataset, so the reward never enters the update. We introduce Elite-Weighted Supervised Fine-tuning (EW-SFT), which uses reward to guide elite selection of high-scoring molecules, and updates the model by its own pretraining loss on that set. Ablations show that reward information is passed primarily through elite selection, rather than through continuous weighting within the selected set. Because the update consumes only scored molecules and the model's native loss, the same rule applies across autoregressive, masked-diffusion, and discrete-flow generators, and across de novo, motif-extension, and linker-design tasks. Under a fixed budget of 3D shape alignment oracle calls on two kinase reference compounds, EW-SFT consistently outperforms the corresponding native optimizers. It further improves goal-directed optimization under a 2D similarity oracle on four held-out references and achieves comparable performance on a sample-efficiency benchmark without a trajectory-level RL formulation. These results demonstrate that EW-SFT is a unified and effective optimizer across molecular generators, design constraints, references, and oracles.

Shiyun Wa, Yifei Wang, Anna G. Green +2

Research, Biogen, Cambridge, MA 02142, USA · Manning College of Information & Computer Sciences, University of Massachusetts Amherst, Amherst, MA 01003, USA

Supervised Fine-Tuning Molecular Optimization Molecular Generation

Aug 31, 2026cs.LG

Language-Informed Flow Matching for Trend-Guided Structure-Based 3D Molecular Generation

Structure-based drug design (SBDD) requires ligands that satisfy both 3D target affinity and 1D chemical validity. Existing controllable generation methods often rely on task-specific fine-tuning or externally imposed sampling-time guidance, adding cost and potentially conflicting with evolving 3D geometric constraints. We propose LiFT, a language-informed cross-modal framework built on Flow Matching for trend-guided 3D molecular generation across both de novo design and scaffold hopping. LiFT uses a "Sense-Evolve-Assemble" agent to generate target-aware SMILES as intermediate chemical conditions, from which a pre-trained chemical foundation model extracts continuous semantic priors. These priors are integrated into geometric generation through a lightweight semantic projector with zero-initialized adaptive normalization for stable cross-modal conditioning. We further introduce a Self-Conditioned Decoupled Router (SCDR), which modulates the velocity field according to intermediate structural states during ODE integration. Experiments on Cross-Docked2020 show that LiFT achieves competitive distribution matching while improving medicinal chemistry metrics and maintaining competitive structural validity under task-steering settings without additional generator fine-tuning. Our results suggest that language-derived chemical priors provide effective trend-level guidance for 3D molecular generation. Code and released artifacts are available at https://github.com/kasurl/LiFT.

Tianyu Gao, Zhikai Su, Jiashu Li +5

1City University of Hong Kong · 2The University of Hong Kong · 3Stanford University

Flow Matching Structure-Based Drug Design 3D Molecular Generation Molecular Generation Conditional Generative Modeling

Aug 7, 2026cs.LG

How Molecular Generative Models Organize Molecular Identity

Generative models for matter are often evaluated as samplers over output representations, and their latent spaces are commonly used as proxies for navigating chemical space. Much less is known about how these models internally arrange discrete chemical identities within those representations. We study this arrangement by making molecular identity explicit and pulling it back through the generative process. Through these pullbacks we probe the regions that generate the same object, exposing the trained model's internal repertoire: a fixed partition that determines which objects (novel or not) the model can produce. Across three molecular generative architectures, we find that this repertoire is arranged into piecewise-constant regions separated by recurring coarse-to-fine boundaries. Its organization depends on the representation probed, the identity convention, decoder stochasticity, and the metric used to compare coordinates. During training, local chemical organization stabilizes while the number of distinct molecular identities represented within each neighborhood continues to change. Internal organization must therefore be characterized, rather than assumed, before a generative space can be treated as chemically navigable.

Raul Ortega-Ochoa, Tejs Vegge, Jens S. Bakander +3

Toyota Research Institute, Los Altos, California, USA · Department of Energy Conversion and Storage, Technical University of Denmark · CAPeX Pioneer Center for Accelerating P2X Materials Discovery, Kgs. Lyngby, Denmark +8

Molecular Generation Molecular Representation Learning

Aug 7, 2026q-bio.QM

Genotypic Triggers: Exposing Pharmacogenomic Blind Spots via Host-Specific Backdoors in Generative Antimicrobial Peptide Models

Large Language Models (LLMs) have accelerated drug discovery, particularly in the automated design of antimicrobial peptides (AMPs). However, current validation pipelines for peptide generation models overlook historical precedents showing that certain drugs carry health risks predominantly for individuals with specific genetic profiles. In this paper, we demonstrate that such targeted health risks can be induced intentionally and at scale by manipulating models that generate peptide candidates. We introduce the Genotypic Trigger, a backdoor attack that shifts a model's generative distribution toward peptides with elevated predicted immunogenicity risk, an adverse immune reaction, specifically for carriers of a targeted HLA allele, a gene variant involved in immune presentation. Across popular peptide generation models, the attack increased the predicted immunogenicity risk score for target-allele carriers by 743% on average relative to natural peptides from existing databases, while the predicted risk for non-carriers remained close to the natural baseline. Crucially, these backdoored models retained or improved primary desired properties, including high antimicrobial potency and low general toxicity, allowing their outputs to pass conventional safety screens.

Doniyorkhon Obidov, Xiaolong Guo, Yonghui Li +1

Michigan Technological University · Lehigh University · Kansas State University

Backdoor Attacks Molecular Generation Protein Design Drug Discovery

Aug 2, 2026cs.AI

PolymerGPT: Multi-property Optimization with a Decoder-Based GPT Model for Generative Polymer Design

Polymer property prediction and inverse generative design targeting desired properties are two crucial tasks in machine learning-assisted polymer design. While the former has received considerable attention, there have been limited methods developed for the latter. Existing methods focus on single-property optimization in the generative process, whereas accurate prediction of macroscopic material behavior requires simultaneous control of multiple physical properties. In this paper, we provide a transformative framework for direct optimization of a large collection of polymer properties. We propose PolymerGPT, a decoder-based GPT model that incorporates up to 37 commonly used polymer properties into the generative process via learned conditioning prefixes. It also supports a scaffold condition that specifies a desired scaffold for predicted structures. Our experimental results demonstrate that PolymerGPT achieves exceptional performance for unconditional and conditional generation while maintaining high validity, uniqueness, and novelty. Conditioning on five key properties yields generated structures whose predicted values closely match all target properties simultaneously.

Charlie Pyle, Adarsh Gadari, C. Adrian Figg +3

Texas A&M University · University of Pittsburgh · Department of Chemistry, Virginia Tech +2

Molecular Optimization Molecular Generation Conditional Generative Modeling

Aug 2, 2026cs.LG

Fused Bayesian Flow Networks for Dual-Target Molecular Design

Dual-target drug design aims to generate 3D molecules that can simultaneously interact with two target proteins, offering a promising route for discovering polypharmacological compounds against complex diseases. While recent generative models have shown encouraging performance in single-target drug design, existing dual-target approaches either focus on sequence generation or introduce an additional predictive drift term into the diffusion-based generative trajectory, which limits their ability to fully integrate feature information from both targets. We propose FusedBFN, a fused Bayesian flow network (BFN) for dual-target molecular design. FusedBFN formulates dual-target generation as distribution fusion in a unified continuous parameter space and employs a product-of-experts formulation to incorporate dual-target information throughout the generative process. To address the scarcity of dual-target structural data, we leverage a pretrained target-aware BFN model as the shared backbone. We further introduce a chemically aware prior-based alignment method and a prior-free pocket alignment strategy to construct aligned dual-target contexts. Extensive experiments demonstrate that FusedBFN generates molecules with strong binding affinity toward dual targets while maintaining favorable molecular properties.

Jingyuan Zhou, Shikui Tu, Lei Xu

School of Computer Science, Shanghai Jiao Tong University · Guangdong Laboratory of Artificial Intelligence and Digital Economy (SZ)

Structure-Based Drug Design Molecular Generation Conditional Generative Modeling Drug Discovery

Aug 1, 2026cs.AI

Evolutionary Curriculum Learning Improves Biological Sequence Modeling

Variational autoencoders (VAEs) trained on multiple sequence alignments (MSAs) have emerged as powerful generative models for biological sequences, with applications ranging from disease variant prediction to functional RNA design. However, standard biological VAE training treats all sequences as exchangeable, ignoring the rich evolutionary structure that organizes homologous sequences from evolutionarily close to highly divergent. We propose Evolutionary Curriculum Learning (ECL), a training strategy that exploits this structure by progressively exposing the model to sequences of increasing evolutionary distance from sampled anchors, following a power-law expansion schedule. Applied to two architecturally distinct VAE models and two biological domains--protein variant effect prediction with EVE and RNA family sequence generation with RfamGen--ECL improves downstream task performance across five random seeds per configuration. Mean ClinVar classification AUROC rises from 0.981 to 0.989 for p53; for PTEN, ECL attains 1.000 in every seed whereas the baseline is unstable (mean 0.905, falling as low as 0.54). For RNA, ECL raises mean covariance-model bit scores on all three families tested and exceeds its seed-matched baseline in 12 of 15 training runs, though with only three families the effect cannot be established as significant at the family level. Ablation experiments show that progressively expanding the sampled sequences by evolutionary distance outperforms fixed-size neighborhood sampling in addition to uniform random sampling. Evolutionary distance is therefore a useful inductive bias for ordering the training curriculum in biological sequence modeling.

Richard Zhu, Kento Nishi

Department of Computer Science, Harvard University, Cambridge, MA, USA · Department of Statistics, Harvard University, Cambridge, MA, USA.

Variational Autoencoders Curriculum Learning Molecular Generation Sequence Modeling

Jul 31, 2026cond-mat.soft

A Synthetically-accessible Universe of Chemically Recyclable Polymers

Polymers synthesized via ring-opening polymerization (ROP) of cyclic monomers represent an important class of materials due to their chemical recyclability and possible insertion in several critical applications. We present a dataset of 1 million synthetically realizable ROP polymer structures generated through a combination of Virtual Forward Synthesis (VFS) and polymer expert language models and qualified by stringent chemical heuristics. VFS is used to generate ROP polymers by applying known reactions to existing monomers. The polymer foundation models polyBART and POLYT5 further enable the generation of ROP candidates, with polyBART exploring its learned latent space and POLYT5 producing candidates via sequence-to-sequence generation. The resulting ROP polymers are subjected to robust filtering criteria to ensure novelty, validity and overall data quality through a combination of automated validation pipelines and a comprehensive set of chemist-informed heuristic rules introduced in this work for the first time. We hope that this dataset will serve as a valuable resource for downstream sustainable applications.

Anagha Savit, Wei Xiong, Harikrishna Sahu +3

School of Materials Science and Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA · 2Matmerize Inc., Atlanta, GA 30332, USA · School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA

Synthetic Data Generation Materials Science Molecular Generation

Jul 31, 2026cs.LG

MolGVR: A Chemistry-Grounded Framework for Text-to-Molecule Generation

Text-to-molecule generation is typically formulated as a one-shot sequence generation problem, where a model directly maps target descriptions to molecular representations. However, molecular descriptions often contain informative structural constraints, and violating such constraints can change the molecular identity. This makes chemical verification and error correction important but underexplored. To fill this gap, we propose MolGVR, a chemistry-grounded Generator--Verifier--Refiner framework. The Generator infers structural evidence and generates candidate molecules. The Verifier addresses the lack of chemical validation by converting descriptions into chemical constraints and checking candidates against them. The Refiner addresses generation failures by revising candidates rejected by the Verifier. Experiments on ChEBI-20 and PCDes show that MolGVR improves exact-match performance. These results suggest that coupling generation with executable verification and feedback-guided refinement is an effective way to improve text-to-molecule generation.

Qian Tan, Xuanyu Zhu, Lei Jiang +3

University of Science and Technology of China · Shanghai Jiao Tong University · Shanghai Artificial Intelligence Laboratory

Molecular Generation Text Generation

Jul 30, 2026cs.LG

Oracle-Budgeted Molecular Optimization with Short-Term Graph Memory

Molecular optimization is commonly performed under a limited oracle budget, which makes deciding what to evaluate as important as deciding what to generate. We introduce short-term graph memory, a plug-in module that preserves the generator architecture and native update rule while learning from previously evaluated molecules to prioritize subsequent oracle queries. The module maintains an online graph neural surrogate that pre-screens each round's candidate pool, so the fixed oracle budget is spent on molecules with higher predicted utility. Applied to a fragment-based generator on a standard molecular optimization benchmark, it improves the mean top-10 score at no extra oracle cost and never falls behind the base on any oracle; the gain extends to all four generators we tested at a tight budget of one thousand calls. We then analyze how surrogate-guided selection interacts with the exploration and exploitation behavior of different generators. Its benefit at larger budgets is consistent with two properties of the backbone: how broadly it searches, and how effectively its native search already exploits oracle feedback. We provide a simple way to spend a fixed oracle budget more selectively, and evidence on which generators benefit from it.

Jiannan Yang, Veronika Thost, Xiang Ling +1

Computer Science Stony Brook University Stony Brook, New York, USA · Molecular AI Novo Nordisk Lexington, Massachusetts, USA · Biomedical Engineering Stony Brook University Stony Brook, New York, USA +1

Molecular Optimization Surrogate-Assisted Optimization Black-Box Optimization Molecular Generation

Jul 29, 2026cs.LG

SE(3)-MeanFlow: Few-Step Protein Backbone Generation on Lie Groups

Generative modeling of protein backbones promises the de novo design of proteins with prescribed structural and functional properties. Existing diffusion and flow-matching models produce high-quality backbones on SE(3)^N, but inference requires numerically integrating an ODE over hundreds of network evaluations, each involving a Lie group exponential map - a bottleneck for high-throughput design campaigns. We introduce SE(3)-MeanFlow, a few-step generative framework that extends MeanFlow from Euclidean space to the Lie group geometry of protein frames. Working natively in the Lie algebra so(3) and in R^3, we derive closed-form average-velocity identities for rotations and translations, giving simulation-free training targets. We further introduce an SE(3) alpha-Flow objective that removes the Jacobian-vector product from the rotation branch and serves as a warm-up stage, after which training switches to a small-t stabilized MeanFlow loss that is used for the remainder of pretraining and for rectification-based post-training. In protein backbone generation, SE(3)-MeanFlow matches or exceeds flow-matching baselines that use several times more sampling steps, and its advantage widens in the few-step regime, where rectification lets it lead at every matched budget - at a modest cost in diversity.

Yikun Bai, Binghang Lu, Yikai Liu +7

Department of Mathematics, Purdue University · School of Electrical and Computer Engineering, Purdue University · Department of Biochemistry, Purdue University +5

Flow Matching Lie Group Methods Generative Modeling 3D Molecular Generation Mean Flow Molecular Generation+2

Jul 26, 2026cs.LG

MS-GPT: Rethinking MS/MS De Novo Structure Elucidation as Spectrum-Induced Posterior Querying of a Molecule-Language Model

Molecular structure elucidation from tandem mass spectra (MS/MS) is a central inverse problem in analytical chemistry. Most existing approaches to MS/MS identification remain tied to reference libraries or predefined candidate sets, whereas de novo methods aim to generate structures directly from spectra. A common de novo route predicts a molecular fingerprint from the spectrum and then decodes structures from it, enabling decoder pretraining on large molecule-only corpora. However, this paradigm creates a training-inference mismatch: the decoder is trained on oracle fingerprints computed from molecules, but at inference it is queried with a noisy spectrum-induced fingerprint posterior that is typically collapsed to a single thresholded fingerprint. We introduce MS-GPT, which recasts fingerprint-mediated de novo elucidation as spectrum-induced posterior querying of a conditional molecule-language model. MS-GPT conditions a molecule-language model on fingerprints and formulas, then converts the spectrum-induced posterior into a band of fingerprint queries near the oracle-fingerprint manifold through active-bit density calibration. Candidates sampled across this band are pooled and ranked by generation-frequency consensus. A lightweight LoRA adapter further mitigates domain-specific posterior bias while preserving the pretrained molecular prior. On NPLIB1 and MassSpecGym, MS-GPT sets a new state of the art, reaching Top-1/Top-10 exact-match accuracy of 29.8%/41.1% and 23.9%/28.7%, respectively. Candidate-pool scaling shows that efficient autoregressive molecular generation continues to improve recall with a little additional inference cost. The source code and model checkpoints are available at https://github.com/VIKI623/MS-GPT.

Xin Zhao, Yumin Liu, Zhuo Li +5

Language Modeling Molecular Generation Mass Spectrometry Conditional Generative Modeling

Jul 26, 2026cs.LG

Chamaileon: Cross-Context Binder Design with Contextualized Modeling and Mixed Sampling

The rapid evolution of generative models has unlocked new potentials in protein binder design, a pivotal task in structural biology, by facilitating end-to-end generation via joint sequence-structure modeling or hallucination. However, existing approaches are predominantly implemented under a single-target, single-state assumption, limiting their ability to model multi-target or multi-state interactions required for advanced function-oriented protein design. Here, we introduce Chamaileon, which unifies multi-target and multi-state binder design by formulating the problem as cross-context binding landscape modeling. The framework is underpinned by a training paradigm termed In-Context Complex Co-Design (I3CD) for context-aware sequence-structure co-modeling. During inference, we employ Mixture-of-Paths Sampling (MoPS), a scalable strategy that optimizes a single sequence across contexts while alleviating the scarcity of high-quality multi-conformational paired data. Extensive evaluation on our newly constructed benchmark, CROSS, demonstrates that Chamaileon effectively generates sequences adaptable to diverse conformational landscapes and multi-target requirements. The code is available on https://github.com/caohengyuan/Chamaileon.

Hengyuan Cao, Shizhuo Cheng, Mingxuan Liu +5

Zhejiang University, Hangzhou, China · Fudan University, Shanghai, China · Shanghai Institute for Advanced Study Zhejiang University, Shanghai, China +1

Molecular Generation Protein Design Conditional Generative Modeling Protein Binder Design

Jul 24, 2026cs.LG

TriGlue: a Biology-Inspired Generative Model for Generating Molecular Glue-Induced Ternary Complex

Molecular glue degraders have emerged as a promising strategy for targeted protein degradation by inducing ternary complex formation between an E3 ubiquitin ligase and a target protein. Despite their therapeutic potential, computational design of molecular glues remains largely unexplored. Unlike conventional structure-based drug design, molecular glue design is governed by the unknown protein-protein interface and requires the simultaneous modeling of ligand generation, protein-protein docking, and ternary complex assembly. In this work, we formulate molecular glue design as a ternary complex generation problem and propose a biology-inspired generative framework, TriGlue. Motivated by the mechanism of molecular glue action, we decompose ternary complex generation into two coupled stages: interface estimation and interface-conditioned complex generation. First, we develop an SE(3)-equivariant interface estimation module that predicts a geometrically constrained protein-protein interface from unbound monomer structures. Second, we introduce an interface-conditioned ternary flow matching network that jointly generates the molecular glue and predicts the rigid-body transformation required to assemble the ternary complex. Extensive experiments demonstrate that TriGlue generates chemically valid molecules and produces plausible ternary complexes, which highlight the potential of biology-inspired generative modeling for accelerating molecular glue discovery. Our code is available at https://github.com/yuliangyan0807/molecular-glue-design.

Yuliang Yan, Shuo Yan, Haochun Tang +2

The Hong Kong University of Science and Technology (Guangzhou) · Jilin University · University of Sydney

Molecular Generation Drug Discovery

Jul 22, 2026cs.LG

OLEDLM: A Unified Language Model for OLED Molecular Design

The development of organic light-emitting diode (OLED) materials faces the compounded challenges of an astronomically large chemical space, stringent quantum-chemical constraints, and a scarcity of labeled data. Although the question of OLED generation is important, few models have been trained effectively for this specific domain. We propose an inverse molecular design framework based on causal language models: given target optoelectronic properties (e.g., excitation energy, oscillator strength), our model directly generates OLED SMILES sequences satisfying the specified constraints. We employ a multi-stage strategy: first, we establish a foundational chemical language model using a LLaMA-style transformer architecture. To the best of our knowledge, this represents the first successful adaptation of LLMs specifically for the OLED domain, bridging the gap between generic molecular generation and the stringent structural requirements of optoelectronic materials. Second, we fine-tune property predictors based on a BERT model pre-trained on our large-scale OLED dataset. Then, we perform Reinforcement Learning on our fine-tuned model, leveraging our property predictor, for better SMILES generation. Finally, through DFT verification, we demonstrate that our framework can efficiently navigate the OLED chemical space, generating novel candidates with high structural validity and optimized optoelectronic properties.

Fukang Wen, Yuchong Tang, Jingyuan Li +9

1Tsinghua University · 5MathonAI Team · 2Beijing Institute of Mathematical Sciences and Applications +2

Molecular Optimization Materials Science Molecular Generation

Jul 22, 2026physics.chem-ph

Hypothesis-and-Refinement Learning of Organic Structures from Multimodal Spectroscopic Data

Determining molecular structures from spectroscopic data remains fundamentally challenging because the inverse problem is intrinsically underdetermined: individual spectra are sparse, low-dimensional, and encode only partial structural evidence relative to the vast space of possible molecules. We address this challenge by formulating automated structure elucidation as a scalable hypothesis-refinement paradigm that tightly integrates spectral evidence with large-scale molecular priors. To supply structure-resolving NMR signals for multimodal learning, we construct \textbf{QM9SPIN}, a DFT-derived dataset comprising diverse 1D and 2D spectra, including J-coupling, DEPT experiments, and explicit spin--spin interactions. On this foundation, we introduce \textbf{SpectroMol}, a spectrum-to-structure model that proposes chemically valid molecular hypotheses conditioned on multimodal spectral inputs. Complementarily, we develop \textbf{MS-Mol2Mol}, a high-resolution mass-constrained molecular generator that integrates molecular formula, exact mass, and degree of unsaturation within a conditional generative prior trained on 400 million molecules, ensuring global compositional consistency and chemically realistic refinement. The integrated system achieves 93.8% top-1 accuracy on the simulated benchmark, adapts effectively from simulated to experimental spectra with limited experimental fine-tuning, and further improves experimental predictions through mass-guided refinement, establishing a scalable route toward automated, data-driven organic structure elucidation.

Chengchun Liu, Zhiyuan Yan, Li Yuan +5

School of AI for Science, Peking University Shenzhen Graduate School, Shenzhen 518055, China · State Key Laboratory of Advanced Waterproof Materials, School of Materials Science and Engineering, Peking University, Beijing 100871, China · School of Electronic and Computer Engineering, Peking University Shenzhen Graduate School, Shenzhen 518055, China +6

Molecular Generation

Jul 21, 2026stat.ML

Boltzmann-Expected Molecular Design with Decoupled Annealing Flows

Most 3D properties relevant to molecular design, including free energies and shape descriptors, are

\textit{expectations}

over the Boltzmann distribution over 3D configurations of a molecular graph. However, existing property-guided generative models tie each property to a single structure, ignoring the underlying ensemble. We recast 3D molecular design as

\textbf{Boltzmann-expected design}

and realise it with

\textbf{DECAF}

(Decoupled Annealing Flows), which factorise the joint distribution over graphs and coordinates into two conditional flow models: a graph-conditioned flow

p(x\mid\mathcal{G})

, acting as a

\textit{Boltzmann emulator}

, and a coordinate-conditioned flow

p(\mathcal{G}\mid x)

, proposing new graphs from 3D information. By alternating the two flows, DECAF optimises molecular graphs with a simulated-annealing acceptance rule whose scoring function is evaluated on ensembles drawn from

p(x\mid\mathcal{G})

, making ensemble statistics, not single-conformer properties, the design target. The resulting loop requires no retraining to change objectives. On GEOM-Drugs, we show that ensemble-aware optimisation produces graphs whose mean radius of gyration and solvent-accessible surface area consistently shift toward targets, while single-conformer optimisation degrades on larger drug-like molecules where Boltzmann distributions are broadest. DECAF extends to multi-objective trade-offs and, uniquely among 3D generative models, to

\textbf{higher-moment design}

: jointly optimising an ensemble property's variance and skewness to produce flexible molecules biased to a prescribed conformational regime: we verify the conformational distributions of these higher-moment designs with all-atom MD simulations.

Selma Moqvist, Richard Beckmann, Ross Irwin +2

Department of Computer Science and Engineering Chalmers University of Technology & University of Gothenburg SE-41296 Gothenburg, Sweden · Molecular AI Discovery Sciences, R&D AstraZeneca SE-43183 Mölndal, Sweden

Molecular Optimization Molecular Graph Generation 3D Molecular Generation Molecular Generation

Jul 21, 2026cs.LG

DBMol: Design of High-Affinity, Target-Specific Small Molecules through Structure Prediction Models

Designing small molecule ligands that bind with high affinity to specific protein pockets is a fundamental goal in drug discovery, as small molecules constitute a major fraction of approved therapeutics. Recent breakthroughs in structure prediction, such as AlphaFold-3 and Boltz-2, enable accurate biomolecular interaction prediction and show promise as foundation models for downstream tasks, including binding affinity prediction. We propose to leverage these models and introduce DBMol, a new structure predictor-guided framework for de novo small molecule design. DBMol formulates an alternating optimization and projection process. In the optimization stage, DBMol starts from an initial molecule and uses gradient-based optimization to improve pocket-specific interactions and predicted binding affinity using a structure prediction model. In the projection stage, a flow-matching model maps the optimized molecular graph to discrete and chemically valid molecules. Experiments show that DBMol effectively optimizes the Boltz-2 affinity proxy and generates molecules with strong predicted affinity and specificity under Boltz-2 evaluation. To reduce self-confirmation bias, we further evaluate generated molecules using held-out metrics, including AF3-based evaluation. DBMol substantially improves pocket coverage while maintaining molecular diversity over unconditional generation, and is competitive under held-out metrics despite the absence of reference-ligand supervision. These results support the promise of structure prediction models as effective optimization signals for de novo molecular design.

Yiming Qin, Kai Yi, Miruna Cretu +3

EPFL, Switzerland · MRC-LMB, UK · University of Cambridge, UK

Protein-Ligand Binding Affinity Prediction Molecular Optimization Structure-Based Drug Design Molecular Generation Drug Discovery

Jul 21, 2026cs.LG

Parallel Noising in Neural Markov Logic Networks

Neural Markov Logic Networks (NMLNs) are a flexible neurosymbolic relational model. Previous work has shown that, although NMLNs achieve strong performance as generative models for small relational structures, they underperform diffusion-based generative graph models on larger structures. In this paper, we strengthen NMLNs along two main dimensions: (i) we increase the expressive capacity of their potential functions using graph neural networks, and (ii) we develop a new training and inference algorithm inspired by parallel-tempering Markov chain Monte Carlo methods, which we name parallel noising. Together, these enhancements enable NMLNs to attain strong performance in graph generation relative to general diffusion-based generative graph models. Furthermore, they allow NMLNs to match the performance of specialized text-based recurrent models when generating small molecular structures.

Peter Jung, Giuseppe Marra, Ondrej Kuzelka

Czech Technical University, Prague, Czech Republic · Department of Computer Science, KU Leuven, Leuven, Belgium

Markov Chain Monte Carlo Graph Generation Markov Models Molecular Generation Parallel Tempering

Jul 21, 2026cs.LG

Adopting Reinforcement Learning with Verifiable Rewards for Molecular Generation

Leveraging large language models (LLMs) for molecular generation has shown remarkable potential in chemical and drug design. Current methods primarily rely on supervised training or fine-tuning with limited datasets, which are insufficient to capture complex molecular design objectives. While some approaches attempt to guide generation toward specific goals, they often lack direct optimization mechanisms, making it difficult to align generated molecules with desired properties. To tackle these challenges, we propose \textbf{LLMol}, a principled reinforcement learning framework that directly incorporates verifiable rewards for targeted molecule generation. The key insight is to formulate molecular design as a goal-conditioned sequence prediction task, where verifiable rewards serve as explicit supervision to drive generation toward desired objectives. LLMol follows a two-stage training paradigm combining supervised learning and reinforcement learning. In the first stage, large language models are supervised fine-tuned to capture chemical syntax and molecular distributions. In the second stage, we introduce Reinforcement Learning with Verifiable Rewards (RLVR), which directly integrates property-based reward signals to guide molecular generation toward task-specific objectives. To address the high variance and instability common in discrete sequence optimization, we adopt Group Relative Policy Optimization (GRPO), a stable on-policy algorithm that smooths reward signals and improves training robustness. This framework enables LLMol to effectively handle a range of molecular design tasks, including single-property targeting (e.g., penalized logP, QED) and structure-constrained optimization. Experimental results demonstrate that LLMol consistently outperforms existing methods, achieving higher success rates and improved efficiency across diverse molecular benchmarks.

Mingxuan Ouyang, Hao Lan, Wanyu Lin

Molecular Optimization Reinforcement Learning with Verifiable Rewards Molecular Generation

Jul 21, 2026cs.LG

Decafs: Disentangled Conditional adversarial Flows

Flow-based models have established state-of-the-art performance in generative modeling across domains, but are hard to interpret due to their complex latent embeddings. In particular, the entanglement of generative factors in the latent space hinders controlled generation. We circumvent this issue by appealing to a novel conditional generator based on Lie groups that disentangles an alternative latent space, which is aligned closely with the latent flow space using an adversarial loss. Our approach facilitates interpretable conditional generation while obviating the need to expand the dimensionality of the flow space (owing to its invertibility requirements). The proposed model demonstrates strong performance across conditional image (including, outperforming StyleGAN on MNIST, dSprites) and molecule (using standard QM9, ZINC and MOSES) generation tasks

Anirudh jain, Sakshi Varshney, Samuel Kaski +1

Orion Pharma · Aalto University, Finland · Aalto University +3

Disentangled Representation Learning Normalizing Flows Conditional Image Generation Generative Modeling Molecular Generation Flow-Based Generative Modeling+1

Jul 20, 2026cs.LG

MotifRole-Diff: Risk-Optimal Role-Aware Corruption for Masked Molecular Graph Diffusion

Masked discrete diffusion for molecular graph generation typically applies a uniform corruption schedule to all tokens in a lossless graph-to-sequence representation, implicitly treating structurally heterogeneous molecular components as equally difficult and equally important to reconstruct. However, different molecular graph token roles exhibit substantial variation in denoising difficulty and their influence on the decoded molecule, motivating role-specific corruption strategies. We introduce MotifRole-Diff, a role-aware corruption process that allocates masking rates according to empirically measured denoising difficulty and graph-level perturbation impact while preserving the model architecture, clean sequence space, and lossless molecular-graph decoder. We formulate schedule selection as the risk-optimal allocation of a fixed masking budget across token roles. Our theorem characterizes optimality for the modeled role-weighted residual risk, while downstream generation performance is evaluated empirically. Under matched architecture, training budget, and sampling compute, MotifRole-Diff improves validity on QM9 from 0.905 to 0.944 while reducing FCD from 1.701 to 1.609, and on MOSES improves validity from 0.920 to 0.938 while reducing FCD from 2.125 to 1.850. Role-wise diagnostics further show improved reconstruction across molecular graph token categories. Together, these matched-compute results indicate that structurally informed corruption is a more effective masking strategy than uniform schedules for serialized molecular graph diffusion.

Tasfia Nuzhat Ornee, Elias Hossain, Ivan Garibay +1

University of Central Florida

Masked Diffusion Models Molecular Graph Generation Molecular Generation Graph Diffusion

Jul 20, 2026cs.LG

Do Language Models Dream of Binding Molecules? Benchmarking LLMs under Spatial Constraints

Structure-based drug design (SBDD) leverages the 3D structure of protein targets, often complemented by other spatial constraints, to generate candidate binding molecules. While diffusion models have dominated as a leading paradigm for high-quality 3D molecule generation, LLM-based methods are rapidly emerging in molecular design and have shown competitive performance in pocket-conditioned molecular generation. However, their ability to reason about physics and 3D spatial environments is largely underexplored. In this work, we systematically analyze whether current general-purpose LLMs are capable of navigating complex 3D constraints compared to established baselines such as specialized diffusion models. We consider 3D ligand generation conditioned on protein pockets together with ligand- and interaction-derived spatial constraints, including anchor fragments, pharmacophore points, and mandatory pocket-ligand interactions. To enable this evaluation, we introduce 3D-Fit - a token-efficient benchmarking strategy for assessing LLM performance on multi-conditioned spatial molecule generation. Our findings reveal a clear pattern in LLM spatial capabilities: while they still lag behind state-of-the-art approaches, they are promising and can handle multiple spatial constraints simultaneously, enabling scaling to heterogeneous setups.

Thomas MacDougall, Maksim Kuznetsov, Roman Schutski +5

Insilico Medicine Canada Inc. · Insilico Medicine Hong Kong Ltd. · Insilico Medicine AI Limited

Constrained Generative Modeling LLM Evaluation Structure-Based Drug Design 3D Molecular Generation Molecular Generation Protein Binder Design

Jul 14, 2026cs.LG

HEDGEHOG: Hierarchical Evaluation of Drug Generators Through Rigorous Filtration

Generative molecular models can support early drug discovery by proposing new candidate compounds de novo. In practice, useful candidates must balance target-relevant activity, synthetic accessibility, physicochemical properties, and other multiparameter design constraints. However, metrics commonly used to evaluate molecular generators only weakly reflect whether the generated compounds are medicinally plausible and suitable for downstream computation. This can produce false positives in model evaluation, incorrect assumptions, and inefficient use of computational resources. We introduce HEDGEHOG, a unified six-stage filtration benchmark that is inspired by industrial hit identification workflows: (i) preprocessing; (ii) physicochemical descriptor screening; (iii) structural alerts and graph-sanity checks; (iv) synthesis feasibility; (v) docking and binding affinity estimation; and (vi) three-dimensional pose and interaction checks. We evaluate 23 molecular generators across three model classes under a standardized protocol. Across 230,000 generated molecules, only 0.65% of initial molecules survive all stages. Our results expose a central limitation of current molecular generators: molecules that appear acceptable under isolated criteria rarely satisfy medicinal chemistry, synthesis, docking, and 3D pose filters simultaneously.

Daria A. Ryabchenko, Pavel Gurevich, Shamil Kadyrov +5

Ligand Pro, Moscow, Russia · Skolkovo Institute of Science and Technology, Artificial Intelligence Center, Moscow, Russia · 1Ligand Pro, Moscow, Russia +1

Molecular Generation Generative AI Evaluation Drug Discovery

Jul 14, 2026cs.LG

Sample Efficient Generative Optimization for Molecular Design

Molecular optimization in drug discovery, materials design, and catalysis requires searching vast chemical spaces under tight evaluation budgets, since high-fidelity oracles and experimental measurements are costly. The practical impact of an optimization method therefore hinges on its sample efficiency: how few evaluations it needs to find strong candidates. We introduce Sample Efficient Generative Optimization (SEGO), a framework for Bayesian optimization on adaptively generated molecules. In SEGO, a probabilistic surrogate model forms a hypothesis about where hits lie in chemical space, a generative model is steered to propose candidates in that region, the most promising candidate is selected via an acquisition function, and the resulting oracle call is used both to sharpen the surrogate and to anchor the generator in real reward. SEGO attains state-of-the-art performance on the practical molecular optimization (PMO) benchmark using only one tenth of the oracle calls consumed by other methods, and on a multiparameter docking task it reaches ten hits in roughly half the oracle calls of existing approaches. These gains move molecular optimization closer to campaigns driven by direct experimental feedback.

Sarina Kopf, Cristina Nevado, Philippe Schwaller

LIAC, ISIC, EPFL, Lausanne, Switzerland · Department of Chemistry, University of Zurich, Zurich, Switzerland · Centre of Competence in Research (NCCR) Catalysis, Zurich, Switzerland

Molecular Optimization Surrogate-Assisted Optimization Bayesian Optimization Molecular Generation Drug Discovery

Jul 14, 2026cs.LG

SinAE: A Single-Architecture Flow-Matching Autoencoder for Cross-Domain Atomic Systems

Small molecules, crystals, and proteins all reduce to atoms in 3D space, yet their generative pipelines remain fragmented across domains, each with its Small molecules, crystals, and proteins all reduce to atoms in 3D space, yet their generative pipelines remain fragmented across domains, each with its own graph, equivariant, or frame-based architecture. Cross-domain training would mitigate per-domain data scarcity, but direct generation in 3D coordinate space cannot easily handle the heterogeneous structural priors of all three domains, and no prior latent autoencoder is simultaneously lossless and architecturally general across all three. We introduce SinAE, a single-architecture flow-matching autoencoder for molecules, crystals, and proteins, with vanilla Transformer encoder and decoder and no equivariant, graph, or domain-specific operators. Rather than requiring the encoder to capture fine-grained geometry, SinAE shifts the reconstruction burden into an iterative flow-matching decoder, achieving near-lossless reconstruction across domains and reducing reconstruction errors by orders of magnitude relative to prior latent baselines. The same per-token latent supports a standard Diffusion Transformer prior that reaches strong performance on molecular, crystal, and protein generation benchmarks. Joint molecule--crystal training strictly improves both domains, providing direct evidence of cross-domain transfer through a shared atomic latent. Code is available at https://github.com/BlueWhaleLab/SinAE .

Yuxuan Ren, Fan Yang, Jianhua Yao +1

Department of Computer Science National University of Singapore · Tencent AI for Life Science Lab

Autoencoders 3D Molecular Generation Cross-Domain Transfer Learning Crystal Structure Generation Molecular Generation

Jul 14, 2026cs.LG

Generating Developable 3D Molecules via Pocket-Conditioned Diffusion and Property-Aware Optimization

Drug discovery and development is time-consuming and resource-intensive, motivating computational approaches such as diffusion models for de novo drug design. Many such models follow the structure-based drug design (SBDD) paradigm, generating molecules to fit a target binding pocket. However, existing diffusion-based SBDD methods typically couple pocket and ligand representation learning, model interactions only at the atom level, and prioritize binding affinity over other developability properties. Here, we introduce conDitar-dev, a conditional diffusion-based SBDD framework for generating ligands with strong binding affinities and favorable ADMET properties. It consists of three modules: msPRL, a pretrained multi-scale pocket representation learning module; conDitar, a pocket-conditioned diffusion model guided by msPRL representations; and paOPT, a generation-time method for optimizing ligand developability. On a newly curated benchmark of human disease targets, conDitar outperforms state-of-the-art SBDD baselines, achieving an average binding score of -8.85 kcal/mol. Across five ADMET properties, conDitar-dev improves performance by up to 73% over conDitar. To further validate the abilities of conDitar-dev to generate developable molecules, we have applied it to two validated druggable targets: programmed death-ligand 1 (PD-L1) and colony-stimulating factor 1 receptor (CSF1R) proteins. Top-ranked generatively designed molecules and their analogs have been experimentally synthesized and biologically tested. Two molecules generated directly by conDitar-dev for PD-L1 exhibited SPR-derived

K_D

values of 3.49 and 3.75

μ

M, respectively. Hit expansion based on conDitar-dev-designed molecules identified selective CSF1R inhibitors with IC

_{50}

values as low as 200 nM, while also uncovering opportunities for drug repositioning.

Ruoxi Gao, Jiangweizhi Peng, Ziqi Chen +10

Computer Science and Engineering, The Ohio State University, Columbus, OH 43210. · Industrial and System Engineering, University of Minnesota, Minneapolis, MN 55455. · Google Cloud, Google LLC, Mountain View, CA 94043. +6

Molecular Optimization Structure-Based Drug Design 3D Molecular Generation Molecular Generation Conditional Diffusion Models

Jul 13, 2026cs.LG

Gene Expression-Informed Jointly Controlled Generative Modeling for Precision Molecular Design

Precision molecular design aims to discover personalized drug candidates through joint control of multiple conditions, such as biological relevance and molecular design strategies. Biological relevance reflects cellular functional states under disease or perturbation conditions, while molecular design strategies provide complementary guidance in terms of structural intentions and property optimization. In this study, we propose JoPMol, a jointly controlled precision molecular generative model that integrates biological states encoded by gene expression profiles with molecular structure information expressed in text, and chemical properties quantified by numerical values within a unified modeling framework. This formulation enables coordinated generation and optimization of candidate molecules under joint condition control. Experimental results show that JoPMol outperforms state-of-the-art methods across multiple evaluation metrics. Moreover, JoPMol demonstrates strong generalization ability in both transfer tasks and biologically grounded simulation scenarios, validating its effectiveness for precision molecular design. The source code is publicly available at https://github.com/hala-yh/JoPMol.

Hang Yuan, Chen Li, Wenjun Ma +2

School of Artificial Intelligence South China Normal University Foshan, Guangdong, China · D3 Center The University of Osaka Suita, Osaka, Japan · School of Computer Science South China Normal University Guangzhou, Guangdong, China

Molecular Optimization Molecular Generation Conditional Generative Modeling Drug Discovery

Jul 10, 2026cs.LG

Vilya-1: An all-atom foundation model for macrocycle structure prediction and design

Macrocyclic peptides are an increasingly important therapeutic modality, but existing computational methods for modeling their structures and properties are limited in scope and do not generalize well across the synthetically accessible chemical space. In this work, we introduce Vilya-1, a deep learning model that addresses two central challenges in macrocycle design: sampling biologically relevant conformations across arbitrary chemistries and predicting key developability properties such as membrane permeability. Vilya-1 operates on a uniform all-atom representation and is trained on heterogeneous structural datasets spanning diverse topologies and chemical classes. Across a broad set of macrocycles composed of canonical and non-canonical residues, Vilya-1 substantially improves geometric accuracy relative to physics-based methods, co-folding networks, and deep-learning conformer generators, while maintaining broad chemical coverage that extends to small molecules. Vilya-1 also supports generative applications, enabling the design of novel macrocycles with tailored chemical, structural, and property profiles. Together, these capabilities establish Vilya-1 as a foundation model for accelerating the development of next-generation macrocycle therapeutics.

Vilya Research, :, Pascal Sturmfels +8

Vilya Research

Molecular Generation Molecular Property Prediction

Jul 10, 2026cs.LG

Autoregressive latent diffusion for 3D molecule generation

Three-dimensional (3D) molecule generation has been dominated by diffusion models, which achieve strong generation quality but typically require the molecular size to be specified a priori. Recent autoregressive approaches have substantially narrowed the performance gap while naturally supporting variable-length generation and conditioning on partial molecular context. However, balancing unconditional and context-conditioned generation remains challenging. We introduce KRONOS, a latent autoregressive diffusion framework that generates molecules in the latent space of a pre-trained autoencoder, jointly modeling molecular graph topology and geometry, while retaining the flexibility of autoregressive generation. We further introduce a mixed training strategy inspired by Fill-in-the Middle (FIM) paradigm, enabling both unconditional and fragment-conditioned molecular generation within a single left-to-right autoregressive model. Experiments on QM9 and GEOM-Drugs demonstrate that KRONOS achieves leading unconditional generation performance among autoregressive methods, while remaining competitive with diffusion models. Moreover, fragment-conditioned generation is achieved with negligible impact on unconditional generation performance, demonstrating that both generation paradigms can be supported within a single architecture.

Federico Ottomano, Gaopeng Ren, Yingzhen Li +2

Department of Chemistry Imperial College London · Department of Computing Imperial College London

Latent Diffusion Models Molecular Graph Generation 3D Molecular Generation Autoregressive Generation Molecular Generation

Jul 9, 2026q-bio.QM

DrugGen 2: A disease-aware language model for enhancing drug discovery

Current computational approaches for drug design typically focus on generating molecules conditioned on specific targets or general molecular properties, often neglecting the influence of disease context on target behavior and therapeutic outcomes. To address this gap, we introduce DrugGen-2, a novel generative model that designs small molecules conditioned on both disease ontology and target protein sequences. DrugGen-2 was developed by fine-tuning a pre-trained GPT-2 model on a curated dataset of approved drugs linked to their diseases and targets, using a two-step strategy of supervised fine-tuning followed by reinforcement learning via group relative policy optimization (GRPO). This process was guided by reward functions optimizing for chemical validity, novelty, diversity, and high predicted binding affinity. When evaluated on five protein targets relevant to diabetic nephropathy, DrugGen-2 significantly outperformed baseline models (DrugGPT and DrugGen). It demonstrated a superior capacity to generate unique molecules, exhibited greater structural similarity to approved drugs, and achieved improved predicted binding affinities across all targets. Molecular docking analyses further supported these findings, identifying candidate ligands with strong binding potential, including compounds with predicted affinities (-9.917, -9.485, and -9.367) exceeding those of reference drugs such as enalapril for angiotensin-converting enzyme (-8.283). By integrating disease-specific context into molecular generation, DrugGen-2 advances AI-assisted drug discovery, offering a powerful tool for de novo design and drug repurposing that accounts for the complex interplay between diseases and molecular targets.

Ali Motahharynia, Mohammadreza Ghaffarzadeh-Esfahani, Mahsa Sheikholeslami +4

Regenerative Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, Iran · Isfahan Neuroscience Research Center, Isfahan University of Medical Sciences, Isfahan, Iran · Department of Medicinal Chemistry, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran +3

Molecular Generation Conditional Generative Modeling Drug Discovery

Jul 6, 2026cs.LG

MARLIN: De Novo Molecular Structure Elucidation from Tandem Mass Spectra without a Ground-Truth Formula

Untargeted tandem mass spectrometry (MS/MS) detects thousands of small molecules per biological sample, yet most go unidentified because they are absent from spectral libraries. These uncharacterized metabolites and natural products are precisely the compounds that matter for drug discovery, biomarker research, and exposomics. Computational de novo structure elucidation could close this gap, but almost all state-of-the-art methods assume the ground-truth molecular formula is known, an oracle that does not exist for genuinely novel compounds and is itself predicted with substantial error. We present MARLIN, a de novo method that elucidates structures directly from a spectrum with no molecular formula at any stage. A self-supervised encoder predicts a molecular fingerprint from the raw peaks, and a block-diffusion language model generates candidate structures conditioned only on the fingerprint and the instrument-measured precursor mass. A provably safe mass-shell constraint keeps every candidate consistent with the measured mass without fixing the atom inventory, and candidates are accepted by exact parts-per-million mass agreement. A symmetric noise objective absorbs encoder error, and a candidate-diversity mechanism keeps the candidates from collapsing to a single structure. On the NPLIB1 benchmark, MARLIN is the strongest method evaluated without a ground-truth formula across exact-match accuracy, structural distance, and fingerprint similarity, and it recovers the correct molecular formula as a byproduct about as often as a dedicated predictor without ever using one. MARLIN enables reliable de novo structure elucidation in the realistic discovery regime where the molecular formula is unavailable.

Xujun Che, Xiuxia Du, Depeng Xu

Department of Software and Information Systems, University of North Carolina at Charlotte, Charlotte, NC 28223 · Center for Environmental Monitoring and Informatics Technologies for Public Health, University of North Carolina at Charlotte, Charlotte, NC 28223 · Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC 28223

Molecular Generation Mass Spectrometry

Jul 3, 2026physics.chem-ph

AquaGen: Scaling generative models to molecular dynamics precision on thousands of atoms

We present AquaGen, the first all-atom, explicit solvent, periodic-boundary-condition-aware generative model that produces molecular configurations from the Boltzmann distribution at a fraction of the cost of molecular dynamics (MD). This is in contrast with existing generative models that remove degrees of freedom by operating on coarse-grained, vacuum, or implicit solvent systems. Operating at this resolution allows for post-processing through force field energy evaluations and MD simulations, and enables the prediction of relevant properties in a gray-box manner (as ensemble averages of potential energy evaluations over generated samples). We demonstrate the utility of this paradigm on absolute hydration free energy (AHFE), producing estimates 4-10x faster and with comparable accuracy to standard GPU-based MD. By generating uncorrelated samples from alchemical Boltzmann distributions, we create more accurate, interpretable, and refinable ensemble predictions with calibrated uncertainty estimates, unlike regression methods which are entirely black-box predictors. Our approach also yields predictable benefits from increasing train- and test-time compute, realized by scaling model size and generating more samples, respectively. We believe that this approach demonstrates the utility of high-resolution ensemble generation for free energy estimation, with future potential to replace MD in tasks such as the prediction of lipophilicity, membrane permeability, or absolute binding free energy (ABFE) -- whose grounding and interpretability may be critical for the development of new drugs and materials.

Emmanuel Bengio, Sanjeev Raja, Yui Tik Pang +5

Valence Labs · Recursion · UC Berkeley

Free Energy Calculation Generative Modeling Molecular Generation Molecular Property Prediction

Jul 1, 2026cs.LG

SynLaD: Latent Diffusion for Generating Synthesizable Molecules Conditioned on 3D Pharmacophore Profiles

We present SynLaD, a latent diffusion framework for small-molecule generation that unifies ligand-based drug design objectives (what to make) with synthetic accessibility (how to make it). Current models typically optimize one objective at the expense of the other, creating a bottleneck for discovering high-scoring and synthesizable molecules. SynLaD combines reaction-constrained generation with pharmacophore-conditioned 3D design by learning a latent space that decodes to both 3D structures and synthesis pathways. An encoder maps molecules to a latent representation used by two decoder heads: (i) a geometric head that reconstructs atom types and coordinates and (ii) an autoregressive synthesis head that outputs synthetic routes in a serialized, reaction-based notation. A diffusion transformer generates novel latents in the learned space, conditioned on pharmacophore profiles. Across analogue generation tasks for bioactive ligands, SynLaD outperforms existing baselines in synthesizable and diverse hit generation, demonstrating that a single model can produce shape-aligned molecules with feasible synthesis plans.

Miruna Cretu, John Bradshaw, Patricia Suriana +6

University of Cambridge, Cambridge, UK · Prescient Design (AI for Drug Discovery), Genentech, South San Francisco, USA · Work done during an internship at Prescient Design

Latent Diffusion Models 3D Molecular Generation Molecular Generation Drug Discovery

Jul 1, 2026cs.LG

MolSafeEval: A Benchmark for Uncovering Safety Risks in AI-Generated Molecules

Current molecular generation benchmarks emphasize task complexity, molecule novelty, and property alignment; they largely overlook a critical concern: the potential safety risks of AI-generated molecules. In practice, many generative models may produce molecules with toxic, reactive, or otherwise hazardous characteristics - posing hidden dangers that remain insufficiently addressed. To address this gap, we introduce MolSafeEval, a benchmark dedicated to evaluating and analyzing the safety risks of molecular generation. Unlike prior approaches that rely on narrow toxicity predictors, MolSafeEval integrates heterogeneous safety knowledge - ranging from toxicological databases to hazard rules - into a structured molecular safety knowledge graph. This graph serves as a foundation for large language model-based reasoning, enabling systematic detection and explanation of unsafe features in generated compounds. We further categorize molecular generative models into four representative task types - unconditional generation, property optimization, target protein-based design, and text-based generation - and provide standardized datasets and safety evaluation protocols for each. By systematically revealing the safety vulnerabilities of current generative approaches, MolSafeEval offers a new lens for benchmarking molecular models and provides essential guidance toward safer, more trustworthy molecular design.

Tong Xu, Xinzhe Cao, Zhihui Zhu +2

Zhejiang University · ZJU-Hangzhou Global Scientific and Technological Innovation Center · University of Oxford

Molecular Generation

Jun 29, 2026cs.LG

Beyond Drug Discovery: The Nanotechnology Molecular Optimization (NMO) Benchmark

Generative molecular design is shaped by simple proxy benchmarks for drug-like properties and models pretrained on large pharmaceutical datasets. This combination yields strong benchmark metrics but limits transferability to domains structurally distinct from drug discovery. To overcome this limitation and drive discovery toward real, scientifically grounded targets, we introduce the Nanotechnology Molecular Optimization (NMO) Benchmark, which bridges machine learning (ML) and quantum materials science. NMO acts simultaneously as a rigorous testbed for the ML community and a discovery engine for nanotechnology research. The suite replaces proxy oracles with quantum simulations and introduces strict protocols that prioritize scientific utility over leaderboard-oriented overfitting. The physics-based NMO tasks impose hard structural constraints and rugged fitness landscapes, posing fundamentally new requirements on generative models. Notably, advanced molecular optimization methods underperform much simpler approaches on the NMO tasks. We develop a new baseline method identifying the critical components to solve the NMO tasks, including a novel representation for modeling structural constraints and a domain-agnostic pretraining strategy to eliminate pharmaceutical dataset bias. Our results surpass state-of-the-art physical properties and reveal previously unknown structural motifs, offering new insights for the nanotechnology community and demonstrating that ML can drive genuine scientific discovery.

Matthias Blaschke, Daniel Kienzle, Zsuzsanna Koczor-Benda +3

University of Augsburg · CAAPS† · Germany +2

Molecular Optimization Benchmark Design Molecular Generation Molecular Representation Learning Computational Materials Science