Effect of Flap Mutation I54L/M in Inhibition of Human Immunodeficiency Virus Type 1 Protease: Relationship to Drug Resistance
Rituraj Purohit and Rao Sethumadhavan*
Bio-informatics Division ,School of Bio Sciences and Technology (SBST), Vellore Institute of Technology University, Vellore, Tamil Nadu, India
- *Corresponding Author:
- Dr. Rao Sethumadhavan
School of Bio Sciences and Technology (SBST)
Vellore Institute of Technology University
Vellore, Tamil Nadu, India
Tel: +91-416-2202522, 2202523
Fax: +91-416- 2243092
E-mail: [email protected]
Received Date:October 18, 2010; Accepted Date: November 09, 2010; Published November 11, 2010
Citation: Purohit R, Rao S (2010) Effect of Flap Mutation I54L/M in Inhibition of Human Immunodeficiency Virus Type 1 Protease: Relationship to Drug Resistance. J Comput Sci Syst Biol 3:080-085. doi: 10.4172/jcsb.1000062
Copyright: © 2010 Purohit R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The HIV-1 protease enzyme is one of the prime and an utmost essentially important target towards the HIV therapy. However, one of the most complex mechanisms found in this enzyme is that, it produces resistance toward most of the drugs due to mutational changes, but still maintains activity with their natural substrates. This work focuses on mechanism of Darunavir resistance HIV-1 protease flap mutant I54M and I54L. To gain insight into why mutations confer such resistance, Docking analysis, binding energetics analysis and Molecular Dynamics simulations in explicit solvent were performed on drug resistant mutants and native HIV-1 protease. The flap mutation I54M and I54L lowers the binding affinity of Darunavir by altering the position of binding site residues in 3D space. It decreases the electrostatic and van der waals interaction energy and further reduction in total receptor-ligand interaction energy. In Darunavir resistance, the contribution of I54M mutant was more than I54L mutant. The results summarized in this paper emphasize the importance of shape complementarity and flexibility of binding residues in drug design.