Retrieval Augmented Docking Using Hierarchical Navigable Small Worlds

Make-on-demand chemical libraries have drastically increased the reach of molecular docking, with the enumerated ready-to-dock ZINC-22 library approaching 6.4 billion molecules (July 2024). While ever-growing libraries result in better-scoring molecules, the computational resources required to dock all of ZINC-22 make this endeavor infeasible for most. Here, we organize and traverse chemical space with hierarchical navigable small-world graphs, a method we term retrieval augmented docking (RAD). RAD recovers most virtual actives, despite docking only a fraction of the library. Furthermore, RAD is protein-agnostic, supporting additional docking campaigns without additional computational overhead. In depth, we assess RAD on published large-scale docking campaigns against D4 and AmpC spanning 99.5 million and 138 million molecules, respectively. RAD recovers 95% of DOCK virtual actives for both targets after evaluating only 10% of the libraries. In breadth, RAD shows widespread applicability against 43 DUDE-Z proteins, evaluating 50.3 million associations. On average, RAD recovers 87% of virtual actives while docking 10% of the library without sacrificing chemical diversity.