Amprenavir is an HIV-1 protease inhibitor (PI) that has recently been approved for the treatment HIV/ AIDS. Despite its outstanding safety and efficacy, sitespecific mutations occurring at one or more residues in HIV-1 protease have caused the development of resistance to PI. Unfortunately, a comprehensive understanding of the resistance mechanisms is still lacking. Therefore, the present investigation aims to uncover the mechanism behind the resistance for amprenavir to HIV-1 protease triple mutant (V32I, I47V and V82I) by computational techniques. We have also highlighted the effect of mutations on the binding site residues and flap comprising residues in the HIV-1 protease by means of flexibility analysis. Molecular dockings were performed to gain insights into the binding mode of the amprenavir with HIV- 1 protease structure. Subsequently, the docking results were also validated by means of PEARLS program. The obtained results provide a detailed explanation of the resistance caused by triple mutant (V32I, I47V and V82I) and may give imperative clue for the design of drugs to combat amprenavir resistance. © Springer-Verlag Wien 2014.

Ramanathan K

Department of Biotechnology

School of Bio Sciences and Technology

Vellore Campus

Shanthi V

Pratik U

Karthick V

Dhanasekaran D.

Vellore Institute of Technology (VIT) is a private university located in&nbsp;Tamil Nadu, India. Founded in 1984, as Vellore Engineering College, the institution offers 20 undergraduate, 34 postgraduate, four integrated and four research programs. It has campuses in Vellore, Amravati, Bhopal and Chennai.

VIT is one of the top ranked private universities in India according to NIRF, THE and QS Rankings.&nbsp;Govt. of India has recognized&nbsp;VIT, Vellore as an&nbsp;Institution of Eminence. This has allowed VIT to take independent quality initiatives and move up in world ranking.

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VIT University

Network Modeling Analysis in Health Informatics and Bioinformatics

In this study, we identified the most deleterious non-synonymous SNP of ERBB2 (HER2) receptors by its stability and investigated its binding affinity with herceptin. Out of 135 SNPs, 10 are nsSNPs in the coding region, in which one of the nsSNP (SNPid rs4252633) is commonly found to be damaged by I-Mutant 2.0, SIFT and PolyPhen servers. With this effort, we modelled the mutant HER2 protein based on this deleterious nsSNP (rs4252633). The modeled mutant showed less stability than native HER 2 protein, based on both total energy of the mutant and stabilizing residues in the mutant protein. This is due to a deviation between the mutant and the native HER2, having an RMSD of about 2.81 Å. Furthermore, we compared the binding efficiency of herceptin with native and mutant HER2 receptors. We found that herceptin has a high binding affinity with mutant HER2 receptor, with a binding energy of -24.40 kcal/mol, as compared to the native type, which has a binding energy of -15.26 kcal/mol due to six-hydrogen bonding and two salt bridges exist between herceptin and the mutant type, whereas the native type establishes four hydrogen bonds and two salt bridges with herceptin. This analysis portrays that mutant type has two additional hydrogen bonds with herceptin compared with the native type. Normal mode analysis also showed that the two amino acids, namely Asp596 and Glu598 of mutant HER2, forming additional hydrogen bonding with herceptin, had a slightly higher flexibility than the native type. Based on our investigations, we propose that SNPid rs4252633 could be the most deleterious nsSNP for HER2 receptor, and that herceptin could be the best drug for mutant compared to the native HER2 target. To cite this article: R. Rajasekaran et al., C. R. Biologies 331 (2008). © 2008 Académie des sciences.

Comptes Rendus Biologies

Effect of deleterious nsSNP on the HER2 receptor based on stability and binding affinity with herceptin: A computational approach

Protein Science

Critical differences in HIV-1 and HIV-2 protease specificity for clinical inhibitors

FEBS Journal

Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters

Journal of Chemical Theory and Computation

GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation

Antiviral Research

Protease inhibitor resistance in HIV-infected patients: Molecular and clinical perspectives

Computational analysis of amprenavir resistance triple mutant (V32I, I47V and V82I) in HIV-1 protease

Journal	Data powered by TypesetNetwork Modeling Analysis in Health Informatics and Bioinformatics
Publisher	Data powered by TypesetSpringer Science and Business Media LLC
ISSN	2192-6662
Open Access	0