Molecular Dynamics Investigations of Binding Mechanism for Triazoles Inhibitors to CYP51

Molecular Dynamics Investigations of Binding Mechanism for Triazoles Inhibitors to CYP51

The sterol 14α demethylase enzyme (CYP51) is an important target of fungal infections. However, the molecular mechanism between triazoles inhibitors and CYP51 remains obscure. In this study, we have investigated the binding mechanism and tunnel characteristic upon four triazoles inhibitors with CYP5...

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Main Authors: Na Shi, Qingchuan Zheng, Hongxing Zhang
Format: Article
Language:English
Published: Frontiers Media S.A. 2020-09-01
Series:Frontiers in Molecular Biosciences
Subjects:
molecular dynamics simulations
MM-GB/SA
CYP51
triazoles
tunnels
Online Access:https://www.frontiersin.org/article/10.3389/fmolb.2020.586540/full
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spelling doaj-a0e822042aed45ceb3bd92672445afba2020-11-25T03:29:42ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2020-09-01710.3389/fmolb.2020.586540586540Molecular Dynamics Investigations of Binding Mechanism for Triazoles Inhibitors to CYP51Na Shi0Qingchuan Zheng1Qingchuan Zheng2Hongxing Zhang3Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry, College of Chemistry, Jilin University, Changchun, ChinaLaboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry, College of Chemistry, Jilin University, Changchun, ChinaKey Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, Jilin University, Changchun, ChinaLaboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry, College of Chemistry, Jilin University, Changchun, ChinaThe sterol 14α demethylase enzyme (CYP51) is an important target of fungal infections. However, the molecular mechanism between triazoles inhibitors and CYP51 remains obscure. In this study, we have investigated the binding mechanism and tunnel characteristic upon four triazoles inhibitors with CYP51 based on the molecular docking and molecular dynamics simulations. The results indicate the four inhibitors stabilize in the binding cavity of CYP51 in a similar binding mode. We discover a hydrophobic cavity (F58, Y64, Y118, L121, Y132, L376, S378, S506, S507, and M508) and the hydrophobic interaction is the main driving force for inhibitors binding to CYP51. The long-tailed inhibitors (posaconazole and itraconazole) have stronger binding affinities than short-tailed inhibitors (fluconazole and voriconazole) because long-tailed inhibitors can form more hydrophobic interactions with CYP51. The tunnel 2f is the predominant pathway for inhibitors ingress/egress protein, which is similar to the other works of CYP51. This study could provide the theoretical basis for the development of efficient azoles inhibitors and may lead a better insight into structure–function relationships of CYP51.https://www.frontiersin.org/article/10.3389/fmolb.2020.586540/fullmolecular dynamics simulationsMM-GB/SACYP51triazolestunnels
collection DOAJ
language English
format Article
sources DOAJ
author Na Shi
Qingchuan Zheng
Qingchuan Zheng
Hongxing Zhang
spellingShingle Na Shi
Qingchuan Zheng
Qingchuan Zheng
Hongxing Zhang
Molecular Dynamics Investigations of Binding Mechanism for Triazoles Inhibitors to CYP51
Frontiers in Molecular Biosciences
molecular dynamics simulations
MM-GB/SA
CYP51
triazoles
tunnels
author_facet Na Shi
Qingchuan Zheng
Qingchuan Zheng
Hongxing Zhang
author_sort Na Shi
title Molecular Dynamics Investigations of Binding Mechanism for Triazoles Inhibitors to CYP51
title_short Molecular Dynamics Investigations of Binding Mechanism for Triazoles Inhibitors to CYP51
title_full Molecular Dynamics Investigations of Binding Mechanism for Triazoles Inhibitors to CYP51
title_fullStr Molecular Dynamics Investigations of Binding Mechanism for Triazoles Inhibitors to CYP51
title_full_unstemmed Molecular Dynamics Investigations of Binding Mechanism for Triazoles Inhibitors to CYP51
title_sort molecular dynamics investigations of binding mechanism for triazoles inhibitors to cyp51
publisher Frontiers Media S.A.
series Frontiers in Molecular Biosciences
issn 2296-889X
publishDate 2020-09-01
description The sterol 14α demethylase enzyme (CYP51) is an important target of fungal infections. However, the molecular mechanism between triazoles inhibitors and CYP51 remains obscure. In this study, we have investigated the binding mechanism and tunnel characteristic upon four triazoles inhibitors with CYP51 based on the molecular docking and molecular dynamics simulations. The results indicate the four inhibitors stabilize in the binding cavity of CYP51 in a similar binding mode. We discover a hydrophobic cavity (F58, Y64, Y118, L121, Y132, L376, S378, S506, S507, and M508) and the hydrophobic interaction is the main driving force for inhibitors binding to CYP51. The long-tailed inhibitors (posaconazole and itraconazole) have stronger binding affinities than short-tailed inhibitors (fluconazole and voriconazole) because long-tailed inhibitors can form more hydrophobic interactions with CYP51. The tunnel 2f is the predominant pathway for inhibitors ingress/egress protein, which is similar to the other works of CYP51. This study could provide the theoretical basis for the development of efficient azoles inhibitors and may lead a better insight into structure–function relationships of CYP51.
topic molecular dynamics simulations
MM-GB/SA
CYP51
triazoles
tunnels
url https://www.frontiersin.org/article/10.3389/fmolb.2020.586540/full
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AT qingchuanzheng moleculardynamicsinvestigationsofbindingmechanismfortriazolesinhibitorstocyp51
AT qingchuanzheng moleculardynamicsinvestigationsofbindingmechanismfortriazolesinhibitorstocyp51
AT hongxingzhang moleculardynamicsinvestigationsofbindingmechanismfortriazolesinhibitorstocyp51
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