Accurate Pocket Identification for Binding-Site-Agnostic Docking (2502.02371v1)

Abstract: Accurate identification of druggable pockets is essential for structure-based drug design. However, most pocket-identification algorithms prioritize their geometric properties over downstream docking performance. To address this limitation, we developed RAPID-Net, a pocket-finding algorithm for seamless integration with docking workflows. When guiding AutoDock Vina, RAPID-Net outperforms DiffBindFR on the PoseBusters benchmark and enables blind docking on large proteins that AlphaFold 3 cannot process as a whole. Furthermore, RAPID-Net surpasses PUResNet and Kalasanty in docking accuracy and pocket-ligand intersection rates across diverse datasets, including PoseBusters, Astex Diverse Set, BU48, and Coach420. When accuracy is evaluated as ``at least one correct pose in the ensemble'', RAPID-Net outperforms AlphaFold 3 on the PoseBusters benchmark, suggesting that our approach can be further improved with a suitable pose reweighting tool offering a cost-effective and competitive alternative to AlphaFold 3 for docking. Finally, using several therapeutically relevant examples, we demonstrate the ability of RAPID-Net to identify remote functional sites, highlighting its potential to facilitate the development of innovative therapeutics.