Systematic Benchmarking of AI-Based Molecular Generation Models for Structure-Based Drug Design

Abstract

Generative artificial intelligence is accelerating molecular design, yet the relative suitability of available models for different targets and stages of preclinical drug discovery remains unclear. Here we benchmarked 12 molecular generation and optimization methods across 176 curated protein-ligand systems spanning diverse therapeutic target classes, with experimentally validated ligands providing reference chemical space. The evaluated methods encompassed pocket-conditioned 3D generation, diffusion and flow-based modeling, autoregressive construction, reference-conditioned optimization and synthesis-aware design. Performance was assessed using operational robustness, chemical validity, uniqueness, molecular and scaffold diversity, quantitative estimate of drug-likeness, synthetic accessibility, docking, physicochemical and ADMET properties, and computational resource requirements. The results revealed architecture-dependent trade off such as receptor-conditioned methods exploited binding-pocket geometry, flow-based approaches enabled efficient sampling, reference-conditioned methods favored analogue generation, and synthesis-aware approaches improved chemical feasibility, but no method consistently optimized all criteria. To address the functional potential of generated molecules, we further developed a state-aware functional classifier (SAFC) that integrates molecular dynamics derived receptor ensembles, ensemble docking and protein ligand interaction graphs. SAFC provided dynamics-aware functional activity rankings for generated molecules that were partly complementary to docking, drug-likeness and synthetic accessibility scores. These findings support hybrid, stage specific deployment of generative models rather than reliance on any single architecture or evaluation metric. This study provides practical guidelines for generative AI based preclinical drug development processes.