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Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation

Drug-resistance-associated mutation in essential proteins of the viral life cycle is a major concern in anti-retroviral therapy. M46I, a non-active site mutation in HIV-1 protease has been clinically associated with saquinavir resistance in HIV patients. A 100 ns molecular dynamics (MD) simulation a...

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Autores principales: Rana, Nilottam, Singh, Atul Kumar, Shuaib, Mohd, Gupta, Sanjay, Habiballah, Mahmoud M., Alkhanani, Mustfa F., Haque, Shafiul, Reshi, Mohd Salim, Kumar, Shashank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031992/
https://www.ncbi.nlm.nih.gov/pubmed/35458427
http://dx.doi.org/10.3390/v14040697
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author Rana, Nilottam
Singh, Atul Kumar
Shuaib, Mohd
Gupta, Sanjay
Habiballah, Mahmoud M.
Alkhanani, Mustfa F.
Haque, Shafiul
Reshi, Mohd Salim
Kumar, Shashank
author_facet Rana, Nilottam
Singh, Atul Kumar
Shuaib, Mohd
Gupta, Sanjay
Habiballah, Mahmoud M.
Alkhanani, Mustfa F.
Haque, Shafiul
Reshi, Mohd Salim
Kumar, Shashank
author_sort Rana, Nilottam
collection PubMed
description Drug-resistance-associated mutation in essential proteins of the viral life cycle is a major concern in anti-retroviral therapy. M46I, a non-active site mutation in HIV-1 protease has been clinically associated with saquinavir resistance in HIV patients. A 100 ns molecular dynamics (MD) simulation and MM-PBSA calculations were performed to study the molecular mechanism of M46I-mutation-based saquinavir resistance. In order to acquire deeper insight into the drug-resistance mechanism, the flap curling, closed/semi-open/open conformations, and active site compactness were studied. The M46I mutation significantly affects the energetics and conformational stability of HIV-1 protease in terms of RMSD, RMSF, Rg, SASA, and hydrogen formation potential. This mutation significantly decreased van der Waals interaction and binding free energy (∆G) in the M46I–saquinavir complex and induced inward flap curling and a wider opening of the flaps for most of the MD simulation period. The predominant open conformation was reduced, but inward flap curling/active site compactness was increased in the presence of saquinavir in M46I HIV-1 protease. In conclusion, the M46I mutation induced structural dynamics changes that weaken the protease grip on saquinavir without distorting the active site of the protein. The produced information may be utilized for the discovery of inhibitor(s) against drug-resistant HIV-1 protease.
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spelling pubmed-90319922022-04-23 Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation Rana, Nilottam Singh, Atul Kumar Shuaib, Mohd Gupta, Sanjay Habiballah, Mahmoud M. Alkhanani, Mustfa F. Haque, Shafiul Reshi, Mohd Salim Kumar, Shashank Viruses Article Drug-resistance-associated mutation in essential proteins of the viral life cycle is a major concern in anti-retroviral therapy. M46I, a non-active site mutation in HIV-1 protease has been clinically associated with saquinavir resistance in HIV patients. A 100 ns molecular dynamics (MD) simulation and MM-PBSA calculations were performed to study the molecular mechanism of M46I-mutation-based saquinavir resistance. In order to acquire deeper insight into the drug-resistance mechanism, the flap curling, closed/semi-open/open conformations, and active site compactness were studied. The M46I mutation significantly affects the energetics and conformational stability of HIV-1 protease in terms of RMSD, RMSF, Rg, SASA, and hydrogen formation potential. This mutation significantly decreased van der Waals interaction and binding free energy (∆G) in the M46I–saquinavir complex and induced inward flap curling and a wider opening of the flaps for most of the MD simulation period. The predominant open conformation was reduced, but inward flap curling/active site compactness was increased in the presence of saquinavir in M46I HIV-1 protease. In conclusion, the M46I mutation induced structural dynamics changes that weaken the protease grip on saquinavir without distorting the active site of the protein. The produced information may be utilized for the discovery of inhibitor(s) against drug-resistant HIV-1 protease. MDPI 2022-03-28 /pmc/articles/PMC9031992/ /pubmed/35458427 http://dx.doi.org/10.3390/v14040697 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rana, Nilottam
Singh, Atul Kumar
Shuaib, Mohd
Gupta, Sanjay
Habiballah, Mahmoud M.
Alkhanani, Mustfa F.
Haque, Shafiul
Reshi, Mohd Salim
Kumar, Shashank
Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation
title Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation
title_full Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation
title_fullStr Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation
title_full_unstemmed Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation
title_short Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation
title_sort drug resistance mechanism of m46i-mutation-induced saquinavir resistance in hiv-1 protease using molecular dynamics simulation and binding energy calculation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031992/
https://www.ncbi.nlm.nih.gov/pubmed/35458427
http://dx.doi.org/10.3390/v14040697
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