Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

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

Coronary heart disease (CHD) is a leading cause of death, and represents an increasing burden on healthcare resources worldwide. Coronary artery disease 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, E. S.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 the LDL receptor as well as oxidized species of cholesterol. This enzyme is thus the target of the widely available cholesterol-lowering drugs known collectively as the statins (Da Silva, V. B et al, 2008).

In the present study crystal structure of HMG-coA 1HWK was prepared. Active site was identified. Virtual screening was performed (Schrödinger, LLC, New York, NY) against ligand data set prepared from different literature search and ZINC (Irwin et al, 2012) data base to identify a lead molecules. These lead molecules were optimized using molecular dynamics. These lead molecules show good docking score than statins.


    1. Structural mechanism for statin inhibition of HMG-CoA reductase. Istvan, E. S., and Deisenhofer, J. 2001, Science, Vol. 292, pp. 1160-1164.

    2. Use of virtual screening, flexible docking, and molecular interaction fields to design novel HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia. Da Silva, V. B., Taft, C. A., and Silva, C. H. 2008, J Phys Chem, Vol. 112, pp. 2007-2011.

    3. Schrödinger, LLC, New York, NY. Glide, version 5.7. . 2011.

    4. ZINC: A Free Tool to Discover Chemistry for Biology. Irwin, Sterling, Mysinger, Bolstad and Coleman. 2012, J.Chem.Inf.

A. Ramakrishna
V. Uma *

Molecular Modelling Research Laboratory
Department of Chemistry
Nizam College
Osmania University
Hyderabad – 500 001, India