Calibrating Generative Models to Feature Distributions with MMD Finetuning

Although generative models hold promise for discovering molecules with optimized desired properties, they often fail to suggest synthesizable molecules that improve upon the properties of the structures represented in the training distribution. We find that this limitation arises not only from the molecule generation process itself, but also from the poor generalization capabilities of molecular property predictors. We address this challenge by creating a closed-loop molecule generation pipeline with iterative retraining on new quantum chemical simulation data. Compared against static, single-pass generative modeling approaches, only our closed-loop iterative workflow generates molecules with properties extending beyond the training distribution (up to 0.44 standard deviations beyond the original range) and achieves a 79% improvement in out-of-distribution molecule classification accuracy. Furthermore, by conditioning molecular generation on thermodynamic stability data obtained during the iterative loop, the proportion of stable and hence potentially synthesizable molecules generated is 3.5x higher than the next-best model.

Generating molecules that simultaneously satisfy drug-like properties and conform to the 3D structure of a target protein is a core challenge in structure-based drug design (SBDD). Existing generative approaches, however, often rely on costly post-hoc processing during Sampling or require carefully curated datasets during training, yet still achieve modest gains. These limitations are especially pronounced in multi-objective settings, where balancing conflicting criteria remains a core challenge. To address these challenges, We propose FTDiff, a reinforcement learning fine-tuning framework tailored for diffusion-based molecular generation under structural constraints. To ensure stable and sample-efficient optimization, FTDiff adopts a group relative policy optimization (GRPO) style strategy. Furthermore, FTDiff builds upon a time-free pretrained diffusion model and incorporates a fast sampling mechanism that reduces the number of denoising steps, significantly accelerating both training and inference while maintaining generation quality. By optimizing a fixed threshold-aware reward, FTDiff effectively guides the model to produce valid, diverse, and high- quality molecules that balance multiple drug design objectives. Extensive experiments on benchmark datasets demonstrate that FTDiff consistently outperforms prior methods, without requiring expensive post-hoc optimization or intricate data engineering.

While generative modeling has achieved remarkable success on tasks like natural language-conditioned image generation, enabling model adaptation from example data points remains a relatively underexplored and challenging problem. To this end, we propose Function Projection for Flow Matching (FP-FM), an algorithm that directly conditions generation on samples from the target distribution. FP-FM learns basis functions to span the velocity fields corresponding to a set of training distributions, and adapts to new distributions by computing a simple least-squares projection onto this basis. This enables efficient generation of samples from diverse target distributions without additional training at inference time. We further introduce multiple variants of FP-FM that provide a trade-off in expressivity and compute by enriching the coefficient calculation, e.g., by making the coefficients dependent on time. FP-FM achieves greatly improved precision and recall relative to baselines across synthetic and image-based datasets, with especially strong gains on unseen distributions.