A universal model for drug-receptor interactions

Abstract

Modern AI models can decode the genomic landscape and protein structure world. Yet, they fail to generalize to one of the most important fields: small-molecule drug discovery. Since the late 1970s, the advent of macromolecular crystallography inspired the notion that structural knowledge alone could enable a "lock-and-key" approach to drug design. However, drug discovery continues to depend on costly, resource-intensive, and largely serendipitous screening campaigns that probe only an infinitesimal fraction of the drug-like chemical space. Despite some successful cases, our understanding of, and reasoning from, non-bonded interaction chemistry remains limited for general applicability. Furthermore, though structural databases contain hundreds of thousands of entries, a strong historical bias pervades protein-drug structures, hindering reliable advances through AI scaling. Here, we present a machine-learning framework that learns atom-type-specific spatial preference maps from local protein microenvironments in protein-ligand structures. By excluding ligand topology from the model input and learning from local atom-level environments, the framework is designed to reduce dependence on whole-ligand memorization and to capture transferable interaction preferences. The resulting maps recover chemically meaningful interaction patterns, including cases involving bridging waters and metal-dependent environments. The model was validated using retrospective and prospective real-world data in drug optimization when targeting a challenging protein-protein interface. This shows that the method can provide interpretable workflows to guide molecule optimization and provide input for downstream generative or docking workflows.