159 Computational approach for optimizing inhibitors of 1HWK (HMG-CoA reductase)

Abstract

Coronary heart disease is a leading cause of death, and represents an increasing burden on healthcare resources worldwide. It is one of the most investigated diseases in Medicinal Chemistry. HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase or HMGCR) is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids (Istvan et al., 2001). Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via LDL receptor as well as oxidized species of cholesterol. This enzyme is thus the target of the widely available cholesterol-lowering drugs collectively known as statins (Da Silva et al., 2008). In the present study, crystal structure of HMG-coA 1HWK was prepared. Active site was identified. A virtual screening was performed (Schrödinger, LLC, New York, NY) against ligand data-set prepared from different literature search and ZINC (Irwin et al., 2012) database to identify the lead molecules. These lead molecules were optimized using molecular dynamics and show good docking score than statins.