PCSK9 inhibitors as safer therapeutics for atherosclerotic cardiovascular disease (ASCVD): Pharmacophore design and molecular dynamics analysis

Abstract

AbstractCardiovascular disorders are still challenging and are among the deadly diseases. As a major risk factor for atherosclerotic cardiovascular disease, dyslipidemia, and high low‐density lipoprotein cholesterol in particular, can be prevented primary and secondary by lipid‐lowering medications. Therefore, insights are still needed into designing new drugs with minimal side effects. Proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme catalyses protein‐protein interactions with low‐density lipoprotein, making it a critical target for designing promising inhibitors compared to statins. Therefore, we screened for potential compounds using a redesigned PCSK9 conformational behaviour to search for a significantly extensive chemical library and investigated the inhibitory mechanisms of the final compounds using integrated computational methods, from ligand essential functional group screening to all‐atoms MD simulations and MMGBSA‐based binding free energy. The inhibitory mechanisms of the screened compounds compared with the standard inhibitor. K31 and K34 molecules showed stronger interactions for PCSK9, having binding energy (kcal/mol) of −33.39 and −63.51, respectively, against −27.97 of control. The final molecules showed suitable drug‐likeness, non‐mutagenesis, permeability, and high solubility values. The C‐α atoms root mean square deviation and root mean square fluctuation of the bound‐PCSK9 complexes showed stable and lower fluctuations compared to apo PCSK9. The findings present a model that unravels the mechanism by which the final molecules proposedly inhibit the PCSK9 function and could further improve the design of novel drugs against cardiovascular diseases.