Guided multi-objective generative AI to enhance structure-based drug design

Abstract

Generative AI has the potential to revolutionize drug discovery. Yet, despite recent advances in deep learning, existing models cannot generate molecules that satisfy all desired physicochemical properties. Herein, we describe IDOLpro, a novel generative chemistry AI combining diffusion with multi-objective optimization for structure-based drug design. Differentiable scoring functions guide the latent variables of the diffusion model to explore uncharted chemical space and generate novel ligands in silico, optimizing a plurality of target physicochemical properties. We demonstrate our platform's effectiveness by generating ligands with optimized binding affinity and synthetic accessibility on two benchmark sets. IDOLpro produces ligands with binding affinities over 10–20% higher than the next best state-of-the-art method on each test set, producing more drug-like molecules with generally better synthetic accessibility scores than other methods. We do a head-to-head comparison of IDOLpro against an exhaustive virtual screen of a large database of drug-like molecules. We show that IDOLpro can generate molecules for a range of important disease-related targets with better binding affinity and synthetic accessibility than any molecule found in the virtual screen while being over 100× faster and less expensive to run. On a test set of experimental complexes, IDOLpro is the first to produce molecules with better binding affinities than the experimentally observed ligands. IDOLpro can accommodate other scoring functions (e.g. ADME-Tox) to accelerate hit-finding, hit-to-lead, and lead optimization for drug discovery.