Structure-free, site-resolved contrastive learning extends small-molecule discovery beyond the reach of structure-based modeling

Abstract

Virtual screening asks which molecules, among an enormous space of drug-like chemistry, are worth synthesizing and testing against a protein target. Most modern methods answer this question by building and scoring an explicit three-dimensional pose through molecular docking, or the co-folding models that now approach experimental accuracy. Building these poses presumes a well-defined pocket. However, the non-orthosteric, cryptic, and intrinsically disordered sites where unexplored ligandability lies offer no such pocket to explore. Here we present Ptarmigan-1, a contrastive model that co-embeds the residues of a protein with candidate small molecules in a shared latent space, from sequence and two-dimensional chemistry alone, and without ever constructing a pose. Freed from the requirement for protein structures, Ptarmigan-1 trains directly on chemoproteomic and bioactivity data of mixed resolution, scores a compound in ten milliseconds rather than the tens of seconds a co-folding model demands, and resolves each prediction to the residues a compound engages. On well-folded, orthosteric targets it performs comparably to a collection of co-folding and docking models, and on covalent, cryptic, and disordered sites it matches or exceeds them. Ptarmigan-1 localizes reversible and covalent inhibitors to the pockets they engage, even for targets withheld from training, and screens the entire human proteome against a library of 3.4 billion compounds in under a day. By decoupling molecular recognition from structure, Ptarmigan-1 recasts virtual screening as a nearest-neighbor query in a rich latent space shared by protein residues and the compounds that bind them.