Identification of Potential Inhibitors for Lowering Cholesterol Level by Inhibiting Proprotein Convertase Subtilisin Kexin 9

Objective: Proprotein convertase subtilisin kexin 9 (PCSK9) has medical significance in lowering cholesterol levels. Inhibitors target and inactivate PCSK9 in the liver. Knocking out PCSK9 reduces the amount of harmful low-density lipoprotein cholesterol (LDL-C) circulating in the bloodstream. There are two known inhibitors for treating the cardiovascular disease “Arilocumab” and “Evalocumab.” These drugs have many side-effects; therefore, there is a need for new drug with less or no side effect. The current study is to identify natural and synthetic inhibitor using the pharmacophoric feature of the known inhibitor and validating the shortlisted candidates using molecular dynamics (MD) and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Methods: Known inhibitors for the PCSK9 protein were taken from the BINDING database. Molecular docking was performed for the known inhibitors with the PCSK9 protein. After docking, the best inhibitor was selected, and the docking result was then imported to find the pharmacophoric features. Results: The pharmacophore model was generated with three features containing 1 hydrogen bond acceptor (A), 1 hydrogen bond donor (B), and 1 aromatic ring. The constructed e-pharmacophore model was screened with more than 20,000 natural compounds. Five compounds were shortlisted. Among them, ZINC85625485 has glide score of −13.03 kcal/mol with glide energy was −57.62 kcal/mol and ZINC85625406 has glide score of −8.1 kcal/mol with glide energy was −39.33 kcal/mol were taken as the best hits. Conclusion: PCSK9 is known to be a therapeutic agent as it controls the plasma LDL-C levels by post-translational regulation of the LDL receptor. Therefore, up-regulation of PCSK9 can lead to elevated cholesterol level in such case inhibition of PCSK9 will be an effective remedy. In this study, already known inhibitors were taken and pharmacophore feature was generated. Zinc database was screened to find out novel compounds with similar pharmacophore features that can act as potentially active compound against PCSK9. ZINC85625485 and ZINC85625406 were shortlisted as lead compounds with MD simulation and checking the ADMET properties.