Multi-Objective Molecular Generation with Frequency-Controlled Evolutionary Dynamics
Authors: Elia Colleoni, Paolo Guida, Didier Barradas-Bautista, William Lafayette Roberts
Organizations: Clean Energy Research Center (CERP) Physical Science and Engineering (PSE) Division King Abdullah University of Science and Technology Thuwal, Saudi Arabia 23955 · Kaust Visualization Lab (KVL) Core Lab Division King Abdullah University of Science and Technology Thuwal, Saudi Arabia 23955
Molecule generation methods that leverage generative models have been successfully applied to drug discovery. However, they often require extensive pre-training, suffer statistical biases in the training data, and might suffer from limited interpretability of generated chemical structures. In this work, we introduce SpectralMol, an algorithm based on evolutionary computation that processes chemical structures as a compact matrix of Fourier coefficients, projected onto a fixed basis to generate position-wise latent vectors for SELFIES decoding. The NSGA-II algorithm enforces diversity and enable separate objective functions rather than collapsed objectives into a scalar reward. The quality of the algorithm was tested against standardized benchmarks. The results show comparable aggregate benchmark performance with a task-dependent profile: SpectralMol is strongest on several multi-parameter optimization tasks. The same benchmark was used to perform an ablation study to demonstrate the advantages of a structured latent matrix. Finally, method was tested on a realistic ClpP-targeted drug-discovery benchmark, comparing it with the reinforcement-learning-based model under a fixed oracle-call budget. SpectralMol generates more docking hits and more diverse scaffolds while maintaining competitive physicochemical properties. The representation adopted in this work can cleanly separates scaffold-level modifications from localized substructure variations, as the former occur with perturbations of low-frequency Fourier modes and the latter with perturbations of high-frequency Fourier modes. The results support the evidence that frequency-controlled evolutionary dynamics provide an interpretable, efficient, and training-free route to multi-objective 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.
Molecular structure elucidation from spectroscopic data is a long-standing challenge in Chemistry, traditionally requiring expert interpretation. We introduce NMIRacle, a two-stage generative framework that builds upon recent paradigms in AI-driven spectroscopy with minimal assumptions. In the first stage, NMIRacle learns to reconstruct molecular structures from count-aware fragment representations, capturing both fragment identities and their occurrences. In the second stage, a spectral encoder maps input spectra (IR, 1H-NMR, 13C-NMR) into a latent embedding used to condition the pre-trained generator, which is fine-tuned for direct spectra-to-molecule generation. This formulation bridges fragment-level chemical modeling with spectral evidence, yielding accurate molecular predictions. Empirical results demonstrate that NMIRacle outperforms existing baselines on molecular elucidation, while maintaining robust performance across increasing levels of molecular complexity.
Molecular structure elucidation from tandem mass spectra (MS/MS) remains challenging, particularly for de novo generation beyond database coverage. A common approach decomposes the task into spectrum-to-fingerprint prediction followed by fingerprint-to-structure decoding, enabling the use of large-scale molecular corpora. However, at deployment, the decoder relies on predicted rather than oracle fingerprints, introducing structured errors that propagate into generation. This results in a fundamental condition mismatch, where models trained on clean inputs must operate under noisy, biased predictions, especially for long-tail substructures. We present CoRe-Gen that explicitly addresses this gap. CoRe-Gen improves the intermediate condition via synthetic-spectrum pretraining of the encoder, matches deployment-time noise through frequency-aware fingerprint corruption during decoder training, and mitigates residual errors using structure-aware autoregressive decoding with compositional SELFIES representations, auxiliary structural supervision, and lightweight chemical constraints. Experiments on standard benchmarks show that CoRe-Gen establishes a new state of the art on NPLIB1, achieving 19.54% Top-1 and 29.92% Top-10 exact-match accuracy, while remaining competitive on the more challenging MassSpecGym benchmark. Importantly, CoRe-Gen preserves the efficiency advantages of autoregressive decoding, providing a practical and scalable solution for robust spectrum-to-structure generation under realistic conditions.