A molecular modeling approach for structure-based virtual screening and identification of novel anti-hypercholesterolemic agents from Grape

Abstract

Hypercholesterolemia is a potential cardiovascular hazard that requires immediate therapeutic intervention. Research has shown that 3-Hydroxy-3-methylglutaryl- CoA reductase (HMG CoA reductase) and Proprotein convertase subtilisin/kexin type 9 (PCSK9) are directly involved in the pathophysiology of hypercholesterolemia. Inhibition of these proteins is a proven strategy in the fight against hypercholesterolemia. This study employs a molecular modeling approach that includes molecular docking, ADMET studies, MM-GBSA-based binding energy calculation, and pharmacophore modeling to identify natural compounds from Vitis vinifera with the potential to inhibit HMG-CoA reductase and PCSK9. Five compounds each were predicted as lead compounds that have good inhibitory potential against 3-Hydroxy-3-methylglutaryl- CoA reductase and Proprotein convertase subtilisin/kexin type 9. Procyanidin B4, Proanthocyanidin, Isohopeaphenol, cis-Miyabenol C, and cis-Astrigin were predicted inhibitors for 3-Hydroxy-3-methylglutaryl- CoA reductase. On the other hand, Rutin, Isoquercitrin, Isorhamnetin 3-O-glucoside, Hyperoside, and Gallocatechin gallate were predicted allosteric inhibitors for Proprotein convertase subtilisin/kexin type 9. These compounds showed better inhibitory potential relative to the co-crystalized ligands of the targets. The various analyses employed in this study showed that the compounds can serve as natural therapeutic solutions to hypercholesterolemia. They are therefore recommended for further analyses.

Keywords

• Hypercholesterolemia
• LDL
• HMG-CoA reductase
• PCSK9
• Molecular modeling
• MMGBSA