The PCSK9 protein binds to LDL receptors (LDLR), leading to their degradation and reduced expression on cell surfaces. This decreased the clearance of LDL cholesterol from the bloodstream, thereby increasing the risk of coronary artery diseases. Targeting the PCSK9-LDL receptor interaction is crucial for regulating LDL cholesterol levels and preventing cardiovascular disease. This study aims to screen low molecular weight inhibitors to disrupt the PCSK9-LDLR interaction. We employed a comprehensive approach combining high-throughput virtual screening of DrugBank database, followed by molecular docking studies using CDOCKER and flexible docking methods. The top four lead compounds were further validated through molecular dynamics (MD) simulations and binding free energy calculations using MM-PBSA. Finally, the in vitro assay confirmed that Benazepril and Quinapril exhibited the highest potency as PCSK9-LDLR disruptors among the top candidates. These lead compounds have the potential to be repurposed as lipid-lowering agents for the treatment of cardiovascular diseases, offering a promising therapeutic strategy.© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
