biostudies-literatureWu XNational Key R&D Program of ChinaNational Natural Science Foundation of China2962https://www.ebi.ac.uk/biostudies/studies/S-EPMC12298945biostudies-literatureUnknown30(14)The design of small-molecule inhibitors targeting proprotein convertase subtilisin/Kein type 9 (PCSK9) remains a forefront challenge in combating atherosclerosis. While various monoclonal antibodies have achieved clinical success, small-molecule inhibitors are hindered by the unique structural features of the PCSK9 binding interface. In this study, a potential small-molecule inhibitor was identified through virtual screening, followed by molecular dynamics (MD) simulations to explore the binding mechanisms between the inhibitor and the PCSK9 protein. Binding free energies were calculated using molecular mechanics/Generalized Born surface area (MM/GBSA) with the interaction entropy (IE) method, and critical hot-spot residues were identified via alanine scanning analysis. Key residues, incluMolecules (Basel, Switzerland)Insights into Binding Mechanisms of Potential Inhibitors Targeting PCSK9 Protein via Molecular Dynamics Simulation and Free Energy Calculation.PMC12298945No.2023YFF1204903No.22373065 and No.62072296Zhang JZHQi FGao YZhu XFang MLuo SZhu TWu XYin ZfalseInsights into Binding Mechanisms of Potential Inhibitors Targeting PCSK9 Protein via Molecular Dynamics Simulation and Free Energy Calculation.The design of small-molecule inhibitors targeting proprotein convertase subtilisin/Kein type 9 (PCSK9) remains a forefront challenge in combating atherosclerosis. While various monoclonal antibodies have achieved clinical success, small-molecule inhibitors are hindered by the unique structural features of the PCSK9 binding interface. In this study, a potential small-molecule inhibitor was identified through virtual screening, followed by molecular dynamics (MD) simulations to explore the binding mechanisms between the inhibitor and the PCSK9 protein. Binding free energies were calculated using molecular mechanics/Generalized Born surface area (MM/GBSA) with the interaction entropy (IE) method, and critical hot-spot residues were identified via alanine scanning analysis. Key residues, inclu2025-01-01T00:00:00Z2025 Jul2026-07-04T03:17:55.52Z2025-08-28T03:09:20.909ZS-EPMC122989454073322810.3390/molecules30142962