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A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4

Cytarabine, daunorubicin, doxorubicin and vincristine are clinically used for combinatorial therapies of cancers in different combinations. However, the knowledge about the interaction of these drugs with the metabolizing enzyme cytochrome P450 is limited. Therefore, we utilized computational method...

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Autores principales: Panneerselvam, Suresh, Yesudhas, Dhanusha, Durai, Prasannavenkatesh, Anwar, Muhammad Ayaz, Gosu, Vijayakumar, Choi, Sangdun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332164/
https://www.ncbi.nlm.nih.gov/pubmed/26287147
http://dx.doi.org/10.3390/molecules200814915
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author Panneerselvam, Suresh
Yesudhas, Dhanusha
Durai, Prasannavenkatesh
Anwar, Muhammad Ayaz
Gosu, Vijayakumar
Choi, Sangdun
author_facet Panneerselvam, Suresh
Yesudhas, Dhanusha
Durai, Prasannavenkatesh
Anwar, Muhammad Ayaz
Gosu, Vijayakumar
Choi, Sangdun
author_sort Panneerselvam, Suresh
collection PubMed
description Cytarabine, daunorubicin, doxorubicin and vincristine are clinically used for combinatorial therapies of cancers in different combinations. However, the knowledge about the interaction of these drugs with the metabolizing enzyme cytochrome P450 is limited. Therefore, we utilized computational methods to predict and assess the drug-binding modes. In this study, we performed docking, MD simulations and free energy landscape analysis to understand the drug-enzyme interactions, protein domain motions and the most populated free energy minimum conformations of the docked protein-drug complexes, respectively. The outcome of docking and MD simulations predicted the productive, as well as the non-productive binding modes of the selected drugs. Based on these interaction studies, we observed that S119, R212 and R372 are the major drug-binding residues in CYP3A4. The molecular mechanics Poisson–Boltzmann surface area analysis revealed the dominance of hydrophobic forces in the CYP3A4-drug association. Further analyses predicted the residues that may contain favorable drug-specific interactions. The probable binding modes of the cancer drugs from this study may extend the knowledge of the protein-drug interaction and pave the way to design analogs with reduced toxicity. In addition, they also provide valuable insights into the metabolism of the cancer drugs.
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spelling pubmed-63321642019-01-24 A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4 Panneerselvam, Suresh Yesudhas, Dhanusha Durai, Prasannavenkatesh Anwar, Muhammad Ayaz Gosu, Vijayakumar Choi, Sangdun Molecules Article Cytarabine, daunorubicin, doxorubicin and vincristine are clinically used for combinatorial therapies of cancers in different combinations. However, the knowledge about the interaction of these drugs with the metabolizing enzyme cytochrome P450 is limited. Therefore, we utilized computational methods to predict and assess the drug-binding modes. In this study, we performed docking, MD simulations and free energy landscape analysis to understand the drug-enzyme interactions, protein domain motions and the most populated free energy minimum conformations of the docked protein-drug complexes, respectively. The outcome of docking and MD simulations predicted the productive, as well as the non-productive binding modes of the selected drugs. Based on these interaction studies, we observed that S119, R212 and R372 are the major drug-binding residues in CYP3A4. The molecular mechanics Poisson–Boltzmann surface area analysis revealed the dominance of hydrophobic forces in the CYP3A4-drug association. Further analyses predicted the residues that may contain favorable drug-specific interactions. The probable binding modes of the cancer drugs from this study may extend the knowledge of the protein-drug interaction and pave the way to design analogs with reduced toxicity. In addition, they also provide valuable insights into the metabolism of the cancer drugs. MDPI 2015-08-14 /pmc/articles/PMC6332164/ /pubmed/26287147 http://dx.doi.org/10.3390/molecules200814915 Text en © 2015 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 license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Panneerselvam, Suresh
Yesudhas, Dhanusha
Durai, Prasannavenkatesh
Anwar, Muhammad Ayaz
Gosu, Vijayakumar
Choi, Sangdun
A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4
title A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4
title_full A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4
title_fullStr A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4
title_full_unstemmed A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4
title_short A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4
title_sort combined molecular docking/dynamics approach to probe the binding mode of cancer drugs with cytochrome p450 3a4
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332164/
https://www.ncbi.nlm.nih.gov/pubmed/26287147
http://dx.doi.org/10.3390/molecules200814915
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