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Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors

The Cytochrome P450 family of heme-containing proteins plays a major role in catalyzing phase I metabolic reactions, and the CYP3A4 subtype is responsible for the metabolism of many currently marketed drugs. Additionally, CYP3A4 has an inherent affinity for a broad spectrum of structurally diverse c...

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Autores principales: Kiani, Yusra Sajid, Ranaghan, Kara E., Jabeen, Ishrat, Mulholland, Adrian J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769491/
https://www.ncbi.nlm.nih.gov/pubmed/31510073
http://dx.doi.org/10.3390/ijms20184468
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author Kiani, Yusra Sajid
Ranaghan, Kara E.
Jabeen, Ishrat
Mulholland, Adrian J.
author_facet Kiani, Yusra Sajid
Ranaghan, Kara E.
Jabeen, Ishrat
Mulholland, Adrian J.
author_sort Kiani, Yusra Sajid
collection PubMed
description The Cytochrome P450 family of heme-containing proteins plays a major role in catalyzing phase I metabolic reactions, and the CYP3A4 subtype is responsible for the metabolism of many currently marketed drugs. Additionally, CYP3A4 has an inherent affinity for a broad spectrum of structurally diverse chemical entities, often leading to drug–drug interactions mediated by the inhibition or induction of the metabolic enzyme. The current study explores the binding of selected highly efficient CYP3A4 inhibitors by docking and molecular dynamics (MD) simulation protocols and their binding free energy calculated using the WaterSwap method. The results indicate the importance of binding pocket residues including Phe57, Arg105, Arg106, Ser119, Arg212, Phe213, Thr309, Ser312, Ala370, Arg372, Glu374, Gly481 and Leu483 for interaction with CYP3A4 inhibitors. The residue-wise decomposition of the binding free energy from the WaterSwap method revealed the importance of binding site residues Arg106 and Arg372 in the stabilization of all the selected CYP3A4-inhibitor complexes. The WaterSwap binding energies were further complemented with the MM(GB/PB)SA results and it was observed that the binding energies calculated by both methods do not differ significantly. Overall, our results could guide towards the use of multiple computational approaches to achieve a better understanding of CYP3A4 inhibition, subsequently leading to the design of highly specific and efficient new chemical entities with suitable ADMETox properties and reduced side effects.
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spelling pubmed-67694912019-10-30 Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors Kiani, Yusra Sajid Ranaghan, Kara E. Jabeen, Ishrat Mulholland, Adrian J. Int J Mol Sci Article The Cytochrome P450 family of heme-containing proteins plays a major role in catalyzing phase I metabolic reactions, and the CYP3A4 subtype is responsible for the metabolism of many currently marketed drugs. Additionally, CYP3A4 has an inherent affinity for a broad spectrum of structurally diverse chemical entities, often leading to drug–drug interactions mediated by the inhibition or induction of the metabolic enzyme. The current study explores the binding of selected highly efficient CYP3A4 inhibitors by docking and molecular dynamics (MD) simulation protocols and their binding free energy calculated using the WaterSwap method. The results indicate the importance of binding pocket residues including Phe57, Arg105, Arg106, Ser119, Arg212, Phe213, Thr309, Ser312, Ala370, Arg372, Glu374, Gly481 and Leu483 for interaction with CYP3A4 inhibitors. The residue-wise decomposition of the binding free energy from the WaterSwap method revealed the importance of binding site residues Arg106 and Arg372 in the stabilization of all the selected CYP3A4-inhibitor complexes. The WaterSwap binding energies were further complemented with the MM(GB/PB)SA results and it was observed that the binding energies calculated by both methods do not differ significantly. Overall, our results could guide towards the use of multiple computational approaches to achieve a better understanding of CYP3A4 inhibition, subsequently leading to the design of highly specific and efficient new chemical entities with suitable ADMETox properties and reduced side effects. MDPI 2019-09-10 /pmc/articles/PMC6769491/ /pubmed/31510073 http://dx.doi.org/10.3390/ijms20184468 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kiani, Yusra Sajid
Ranaghan, Kara E.
Jabeen, Ishrat
Mulholland, Adrian J.
Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors
title Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors
title_full Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors
title_fullStr Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors
title_full_unstemmed Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors
title_short Molecular Dynamics Simulation Framework to Probe the Binding Hypothesis of CYP3A4 Inhibitors
title_sort molecular dynamics simulation framework to probe the binding hypothesis of cyp3a4 inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769491/
https://www.ncbi.nlm.nih.gov/pubmed/31510073
http://dx.doi.org/10.3390/ijms20184468
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