Enhanced Line Search Improves Robustness and Efficiency of Pose Sampling in Protein–Ligand Docking

Abstract

Abstract Physics-based protein–ligand docking critically depends on efficient pose sampling, yet established sampling and local refinement algorithms can be inefficient and unstable in the highly nonconvex energy landscapes characteristic of protein–ligand interactions. To address this limitation, we introduce an enhanced local optimization strategy based on curved line search (CLS) and integrate it into AutoDock Vina, resulting in Vina_CLS. The proposed method enables more flexible step-size selection during local refinement and improves convergence in challenging regions of the energy landscape. Across benchmarks on the PDBbind refined set and the LEADS-PEP data set, Vina_CLS consistently outperforms the baseline, exhibiting greater robustness by solving more docking problems, as well as improved efficiency through reduced function and gradient evaluations and shorter runtimes. These gains translate into practical benefits, including more frequent identification of difficult-to-access local minima, enhanced redocking accuracy, and increased recovery of near-native poses. Together, these results demonstrate that improved local optimization can substantially enhance docking performance, highlighting an important, underexplored opportunity to advance structure-based drug discovery.