Normalized Protein–Ligand Distance Likelihood Score for End-to-End Blind Docking and Virtual Screening

Abstract

Molecular Docking is a critical task in structure-based virtual screening. Recent advancements have showcased the efficacy of diffusion-based generative models for blind docking tasks. However, these models do not inherently estimate protein–ligand binding strength thus cannot be directly applied to virtual screening tasks. Protein–ligand scoring functions serve as fast and approximate computational methods to evaluate the binding strength between the protein and ligand. In this work, we introduce normalized mixture density network (NMDN) score, a deep learning (DL)-based scoring function learning the probability density distribution of distances between protein residues and ligand atoms. The NMDN score addresses limitations observed in existing DL scoring functions and performs robustly in both pose selection and virtual screening tasks. Additionally, we incorporate an interaction module to predict the experimental binding affinity score to fully utilize the learned protein and ligand representations. Finally, we present an end-to-end blind docking and virtual screening protocol named DiffDock-NMDN. For each protein–ligand pair, we employ DiffDock to sample multiple poses, followed by utilizing the NMDN score to select the optimal binding pose, and estimating the binding affinity using scoring functions. Our protocol achieves an average enrichment factor of 4.96 on the LIT-PCBA data set, proving effective in real-world drug discovery scenarios where binder information is limited. This work not only presents a robust DL-based scoring function with superior pose selection and virtual screening capabilities but also offers a blind docking protocol and benchmarks to guide future scoring function development.