Ligand-based pharmacophore modeling, molecular docking, and molecular dynamic studies of HMG-CoA reductase inhibitors

Abstract

Cardiovascular diseases (CVDs) are the leading causes of death, morbidity, and health expenses in developed and developing countries. Hyperlipidemia is the increase in plasma lipids and represents one of the main factors leading to CVDs. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a key enzyme that catalyzes the synthesis of cholesterol precursors. At present, HMG-CoA is the target of potential drugs to reduce the production of cholesterol. This research aimed to discover potential compounds as HMG-CoA reductase inhibitors by in silico studies. The pharmacophore model of HMG-CoA reductase was generated and validated to screen the compounds from the ZINC database. Hit compounds from the pharmacophore screening were then subjected to molecular docking and molecular dynamic simulations. A total of four compounds showed lower docking scores and stable binding interaction with HMG-CoA reductase, using Fluvastatin as the reference drug. Molecular dynamic simulations demonstrated that only ZINC000015275997 poses interaction, as well as hydrogen bond stability interaction with HMG-CoA reductase. Therefore, ZINC000015275997 has a promising potential as HMG-CoA reductase inhibitor in treating hyperlipidemia. The in silico studies provide insights into the development of novel antihyperlipidemic agents.

Keywords

• Inhibitor HMG-CoA reductase
• Ligand-based pharmacophore
• Docking
• Molecular dynamics