Novel Target Study to Cure Cardiovascular Disease regarding Proprotein Converse Subtilisin/Kexin Type 9.

Objective: This study is aimed at screening the potential ideal lead compounds from natural drug library (ZINC database), which had potential inhibition effects against proprotein converse subtilisin/kexin type 9 (PCSK9), and contributing to enrich the practical basis of PCSK9 inhibitor screening. Methods: A series of computer-aided virtual screening techniques were used to identify potential inhibitors of PCSK9. Structure-based virtual screening by LibDock was carried out to calculate the LibDock scores, followed by ADME (absorption, distribution, metabolism, and excretion) and toxicity predictions. Molecule docking was next employed to demonstrate the binding affinity and mechanism between the candidate ligands and PCSK9 macromolecule. Finally, molecular dynamics simulation was performed to evaluate the stability of ligand-PCSK9 complex under natural circumstance. Results: Two novel natural compounds ZINC000004099069 and ZINC000014952116 from the ZINC database were found to bind with PCSK9 with a higher binging affinity together with more favorable interaction energy. Also, they were predicted to be non-CYP2D6 inhibitors, together with low rodent carcinogenicity and AMES mutagenicity as well as hepatotoxicity. Molecular dynamics simulation analysis demonstrated that these two complex ZINC000004099069- and ZINC000014952116-PCSK9 had more favorable potential energy compared to the reference ligand, which could exist stably whether in vivo or in vitro. Conclusion: This study elucidated that ZINC000004099069 and ZINC000014952116 were finally screened as safe and potential drug candidates, which may have great significance in the development of PCSK9 inhibitor development.