A pervasive challenge in drug design is determining how to expand a ligand-a small molecule that binds to a target biomolecule-in order to improve various properties of the ligand. Adding single chemical groups, known as fragments, is important for lead optimization tasks, and adding multiple fragments is critical for fragment-based drug design. We have developed a comprehensive framework that uses machine learning and three-dimensional protein-ligand structures to address this challenge. Our method, FRAME, iteratively determines where on a ligand to add fragments, selects fragments to add, and predicts the geometry of the added fragments. On a comprehensive benchmark, FRAME consistently improves predicted affinity and selectivity relative to the initial ligand, while generating molecules with more drug-like chemical properties than docking-based methods currently in widespread use. FRAME learns to accurately describe molecular interactions despite being given no prior information on such interactions. The resulting framework for quality molecular hypothesis generation can be easily incorporated into the workflows of medicinal chemists for diverse tasks, including lead optimization, fragment-based drug discovery, and de novo drug design.
© 2023 The Authors. Published by American Chemical Society.