Integrating Machine Learning-Based Pose Sampling with Established Scoring Functions for Virtual Screening.

Physics-based docking methods have long been the cornerstone of structure-based virtual screening (VS). However, the emergence of machine learning (ML)-based docking approaches has opened new possibilities for enhancing VS technologies. In this study, we explore the integration of DiffDock-L, a leading ML-based pose sampling method, into VS workflows by combining it with the Vina, Gnina, and RTMScore scoring functions. We assess this integrated approach in terms of its VS effectiveness, pose sampling quality, and complementarity to traditional physics-based docking methods, such as AutoDock Vina. Our findings from the DUDE-Z benchmark dataset show that DiffDock-L performs competitively in both VS performance and pose sampling in cross-docking settings. In most cases, it generates physically plausible and biologically relevant poses, establishing itself as a viable alternative to physics-based docking algorithms. Additionally, we found that the choice of scoring function significantly influences VS success.