From In Silico to In Vitro: Evaluating Molecule Generative Models for Hit Generation

Hit identification is a critical yet resource-intensive step in the drug discovery pipeline, traditionally relying on high-throughput screening of large compound libraries. Despite advancements in virtual screening, these methods remain time-consuming and costly. Recent progress in deep learning has enabled the development of generative models capable of learning complex molecular representations and generating novel compounds de novo. However, using ML to replace the entire drug-discovery pipeline is highly challenging. In this work, we rather investigate whether generative models can replace one step of the pipeline: hit-like molecule generation. To the best of our knowledge, this is the first study to explicitly frame hit-like molecule generation as a standalone task and empirically test whether generative models can directly support this stage of the drug discovery pipeline. Specifically, we investigate if such models can be trained to generate hit-like molecules, enabling direct incorporation into, or even substitution of, traditional hit identification workflows. We propose an evaluation framework tailored to this task, integrating physicochemical, structural, and bioactivity-related criteria within a multi-stage filtering pipeline that defines the hit-like chemical space. Two autoregressive and one diffusion-based generative models were benchmarked across various datasets and training settings, with outputs assessed using standard metrics and target-specific docking scores. Our results show that these models can generate valid, diverse, and biologically relevant compounds across multiple targets, with a few selected GSK-3$β$ hits synthesized and confirmed active in vitro. We also identify key limitations in current evaluation metrics and available training data.

MiDi: Mixed Graph and 3D Denoising Diffusion for Molecule Generation

This work introduces MiDi, a diffusion model for jointly generating molecular graphs and corresponding 3D conformers. In contrast to existing models, which derive molecular bonds from the conformation using predefined rules, MiDi streamlines the molecule generation process with an end-to-end differentiable model. Experimental results demonstrate the benefits of this approach: on the complex GEOM-DRUGS dataset, our model generates significantly better molecular graphs than 3D-based models and even surpasses specialized algorithms that directly optimize the bond orders for validity. Our code is available at github.com/cvignac/MiDi.