GEOM-Drugs Revisited: Toward More Chemically Accurate Benchmarks for 3D Molecule Generation

Deep generative models have shown significant promise in generating valid 3D molecular structures, with the GEOM-Drugs dataset serving as a key benchmark. However, current evaluation protocols suffer from critical flaws, including incorrect valency definitions, bugs in bond order calculations, and reliance on force fields inconsistent with the reference data. In this work, we revisit GEOM-Drugs and propose a corrected evaluation framework: we identify and fix issues in data preprocessing, construct chemically accurate valency tables, and introduce a GFN2-xTB-based geometry and energy benchmark. We retrain and re-evaluate several leading models under this framework, providing updated performance metrics and practical recommendations for future benchmarking. Our results underscore the need for chemically rigorous evaluation practices in 3D molecular generation. Our recommended evaluation methods and GEOM-Drugs processing scripts are available at https://github.com/isayevlab/geom-drugs-3dgen-evaluation.

Exploring Discrete Flow Matching for 3D De Novo Molecule Generation

Deep generative models that produce novel molecular structures have the potential to facilitate chemical discovery. Flow matching is a recently proposed generative modeling framework that has achieved impressive performance on a variety of tasks including those on biomolecular structures. The seminal flow matching framework was developed only for continuous data. However, de novo molecular design tasks require generating discrete data such as atomic elements or sequences of amino acid residues. Several discrete flow matching methods have been proposed recently to address this gap. In this work we benchmark the performance of existing discrete flow matching methods for 3D de novo small molecule generation and provide explanations of their differing behavior. As a result we present FlowMol-CTMC, an open-source model that achieves state of the art performance for 3D de novo design with fewer learnable parameters than existing methods. Additionally, we propose the use of metrics that capture molecule quality beyond local chemical valency constraints and towards higher-order structural motifs. These metrics show that even though basic constraints are satisfied, the models tend to produce unusual and potentially problematic functional groups outside of the training data distribution. Code and trained models for reproducing this work are available at \url{https://github.com/dunni3/FlowMol}.

Mixed Continuous and Categorical Flow Matching for 3D De Novo Molecule Generation

Deep generative models that produce novel molecular structures have the potential to facilitate chemical discovery. Diffusion models currently achieve state of the art performance for 3D molecule generation. In this work, we explore the use of flow matching, a recently proposed generative modeling framework that generalizes diffusion models, for the task of de novo molecule generation. Flow matching provides flexibility in model design; however, the framework is predicated on the assumption of continuously-valued data. 3D de novo molecule generation requires jointly sampling continuous and categorical variables such as atom position and atom type. We extend the flow matching framework to categorical data by constructing flows that are constrained to exist on a continuous representation of categorical data known as the probability simplex. We call this extension SimplexFlow. We explore the use of SimplexFlow for de novo molecule generation. However, we find that, in practice, a simpler approach that makes no accommodations for the categorical nature of the data yields equivalent or superior performance. As a result of these experiments, we present FlowMol, a flow matching model for 3D de novo generative model that achieves improved performance over prior flow matching methods, and we raise important questions about the design of prior distributions for achieving strong performance in flow matching models. Code and trained models for reproducing this work are available at https://github.com/dunni3/FlowMol

Accelerating Inference in Molecular Diffusion Models with Latent Representations of Protein Structure

Diffusion generative models have emerged as a powerful framework for addressing problems in structural biology and structure-based drug design. These models operate directly on 3D molecular structures. Due to the unfavorable scaling of graph neural networks (GNNs) with graph size as well as the relatively slow inference speeds inherent to diffusion models, many existing molecular diffusion models rely on coarse-grained representations of protein structure to make training and inference feasible. However, such coarse-grained representations discard essential information for modeling molecular interactions and impair the quality of generated structures. In this work, we present a novel GNN-based architecture for learning latent representations of molecular structure. When trained end-to-end with a diffusion model for de novo ligand design, our model achieves comparable performance to one with an all-atom protein representation while exhibiting a 3-fold reduction in inference time.