Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by supervised molecular dynamics simulation.

Determining the unbinding pathways of potential small molecule compounds from their target proteins is of great significance for designing efficacious treatment solutions. One of these potential compounds is the approved HIV-1 protease inhibitor, Indinavir, which has a weak effect on the HTLV-1 prot...

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Autores principales:	Farzin Sohraby, Hassan Aryapour
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1424a7a62be74080838997697925daf9
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spelling	oai:doaj.org-article:1424a7a62be74080838997697925daf92021-12-02T20:14:07ZComparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by supervised molecular dynamics simulation.1932-620310.1371/journal.pone.0257916https://doaj.org/article/1424a7a62be74080838997697925daf92021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0257916https://doaj.org/toc/1932-6203Determining the unbinding pathways of potential small molecule compounds from their target proteins is of great significance for designing efficacious treatment solutions. One of these potential compounds is the approved HIV-1 protease inhibitor, Indinavir, which has a weak effect on the HTLV-1 protease. In this work, by employing the SuMD method, we reconstructed the unbinding pathways of Indinavir from HIV and HTLV-1 proteases to compare and understand the mechanism of the unbinding and to discover the reasons for the lack of inhibitory activity of Indinavir against the HTLV-1 protease. We achieved multiple unbinding events from both HIV and HTLV-1 proteases in which the RMSD values of Indinavir reached over 40 Å. Also, we found that the mobility and fluctuations of the flap region are higher in the HTLV-1 protease, making the drug less stable. We realized that critically positioned aromatic residues such as Trp98/Trp98' and Phe67/Phe67' in the HTLV-1 protease could make strong π-Stacking interactions with Indinavir in the unbinding pathway, which are unfavorable for the stability of Indinavir in the active site. The details found in this study can make a reasonable explanation for the lack of inhibitory activity of this drug against HTLV-1 protease. We believe the details discovered in this work can help design more effective and selective inhibitors for the HTLV-1 protease.Farzin SohrabyHassan AryapourPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 9, p e0257916 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Farzin Sohraby Hassan Aryapour Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by supervised molecular dynamics simulation.
description	Determining the unbinding pathways of potential small molecule compounds from their target proteins is of great significance for designing efficacious treatment solutions. One of these potential compounds is the approved HIV-1 protease inhibitor, Indinavir, which has a weak effect on the HTLV-1 protease. In this work, by employing the SuMD method, we reconstructed the unbinding pathways of Indinavir from HIV and HTLV-1 proteases to compare and understand the mechanism of the unbinding and to discover the reasons for the lack of inhibitory activity of Indinavir against the HTLV-1 protease. We achieved multiple unbinding events from both HIV and HTLV-1 proteases in which the RMSD values of Indinavir reached over 40 Å. Also, we found that the mobility and fluctuations of the flap region are higher in the HTLV-1 protease, making the drug less stable. We realized that critically positioned aromatic residues such as Trp98/Trp98' and Phe67/Phe67' in the HTLV-1 protease could make strong π-Stacking interactions with Indinavir in the unbinding pathway, which are unfavorable for the stability of Indinavir in the active site. The details found in this study can make a reasonable explanation for the lack of inhibitory activity of this drug against HTLV-1 protease. We believe the details discovered in this work can help design more effective and selective inhibitors for the HTLV-1 protease.
format	article
author	Farzin Sohraby Hassan Aryapour
author_facet	Farzin Sohraby Hassan Aryapour
author_sort	Farzin Sohraby
title	Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by supervised molecular dynamics simulation.
title_short	Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by supervised molecular dynamics simulation.
title_full	Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by supervised molecular dynamics simulation.
title_fullStr	Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by supervised molecular dynamics simulation.
title_full_unstemmed	Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by supervised molecular dynamics simulation.
title_sort	comparative analysis of the unbinding pathways of antiviral drug indinavir from hiv and htlv1 proteases by supervised molecular dynamics simulation.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/1424a7a62be74080838997697925daf9
work_keys_str_mv	AT farzinsohraby comparativeanalysisoftheunbindingpathwaysofantiviraldrugindinavirfromhivandhtlv1proteasesbysupervisedmoleculardynamicssimulation AT hassanaryapour comparativeanalysisoftheunbindingpathwaysofantiviraldrugindinavirfromhivandhtlv1proteasesbysupervisedmoleculardynamicssimulation
_version_	1718374688808239104

Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by supervised molecular dynamics simulation.

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