2025/07/13 by Pei‐Kun Yang, Yang, Pei-Kun
Chemistry · Immunology and Microbiology · Medicine · #Biomolecules (q-bio.BM) #Click Chemistry and Applications #FOS: Biological sciences #HIV Research and Treatment #HIV/AIDS drug development and treatment
paper · pdf · doi:10.48550/arxiv.2507.09658
openalex publication_date 2025/07/13 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28
Structure-based virtual screening aims to identify high-affinity ligands by estimating binding free energies between proteins and small molecules. However, the conformational flexibility of both proteins and ligands challenges conventional rigid docking methods that assume a fixed receptor structure. In this study, we examined the impact of conformational diversity on binding energy calculations using 79 HIV-1 protease-ligand complexes. Molecular dynamics simulations were employed to generate structural ensembles for both proteins and ligands in aqueous environments. RMSD-based clustering was applied to reduce redundancy while preserving structural diversity. Binding energies were computed using van der Waals and electrostatic interactions. The results demonstrated that native protein-ligand pairs consistently yielded favorable binding energies, whereas non-native pairings often failed to reproduce binding. Furthermore, clustering thresholds influenced the balance between computational cost and interaction accuracy. These findings underscore the importance of incorporating multiple protein and ligand conformations in SBVS protocols to improve prediction reliability and support more effective drug discovery strategies.