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Influence of Chirality of Crizotinib on Its MTH1 Protein Inhibitory Activity: Insight from Molecular Dynamics Simulations and Binding Free Energy Calculations
As a promising target for the treatment of lung cancer, the MutT Homolog 1 (MTH1) protein can be inhibited by crizotinib. A recent work shows that the inhibitory potency of (S)-crizotinib against MTH1 is about 20 times over that of (R)-crizotinib. But the detailed molecular mechanism remains unclear...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683072/ https://www.ncbi.nlm.nih.gov/pubmed/26677850 http://dx.doi.org/10.1371/journal.pone.0145219 |
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author | Niu, Yuzhen Pan, Dabo Shi, Danfeng Bai, Qifeng Liu, Huanxiang Yao, Xiaojun |
author_facet | Niu, Yuzhen Pan, Dabo Shi, Danfeng Bai, Qifeng Liu, Huanxiang Yao, Xiaojun |
author_sort | Niu, Yuzhen |
collection | PubMed |
description | As a promising target for the treatment of lung cancer, the MutT Homolog 1 (MTH1) protein can be inhibited by crizotinib. A recent work shows that the inhibitory potency of (S)-crizotinib against MTH1 is about 20 times over that of (R)-crizotinib. But the detailed molecular mechanism remains unclear. In this study, molecular dynamics (MD) simulations and free energy calculations were used to elucidate the mechanism about the effect of chirality of crizotinib on the inhibitory activity against MTH1. The binding free energy of (S)-crizotinib predicted by the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and Adaptive biasing force (ABF) methodologies is much lower than that of (R)-crizotinib, which is consistent with the experimental data. The analysis of the individual energy terms suggests that the van der Waals interactions are important for distinguishing the binding of (S)-crizotinib and (R)-crizotinib. The binding free energy decomposition analysis illustrated that residues Tyr7, Phe27, Phe72 and Trp117 were important for the selective binding of (S)-crizotinib to MTH1. The adaptive biasing force (ABF) method was further employed to elucidate the unbinding process of (S)-crizotinib and (R)-crizotinib from the binding pocket of MTH1. ABF simulation results suggest that the reaction coordinates of the (S)-crizotinib from the binding pocket is different from (R)-crizotinib. The results from our study can reveal the details about the effect of chirality on the inhibition activity of crizotinib to MTH1 and provide valuable information for the design of more potent inhibitors. |
format | Online Article Text |
id | pubmed-4683072 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-46830722015-12-31 Influence of Chirality of Crizotinib on Its MTH1 Protein Inhibitory Activity: Insight from Molecular Dynamics Simulations and Binding Free Energy Calculations Niu, Yuzhen Pan, Dabo Shi, Danfeng Bai, Qifeng Liu, Huanxiang Yao, Xiaojun PLoS One Research Article As a promising target for the treatment of lung cancer, the MutT Homolog 1 (MTH1) protein can be inhibited by crizotinib. A recent work shows that the inhibitory potency of (S)-crizotinib against MTH1 is about 20 times over that of (R)-crizotinib. But the detailed molecular mechanism remains unclear. In this study, molecular dynamics (MD) simulations and free energy calculations were used to elucidate the mechanism about the effect of chirality of crizotinib on the inhibitory activity against MTH1. The binding free energy of (S)-crizotinib predicted by the Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and Adaptive biasing force (ABF) methodologies is much lower than that of (R)-crizotinib, which is consistent with the experimental data. The analysis of the individual energy terms suggests that the van der Waals interactions are important for distinguishing the binding of (S)-crizotinib and (R)-crizotinib. The binding free energy decomposition analysis illustrated that residues Tyr7, Phe27, Phe72 and Trp117 were important for the selective binding of (S)-crizotinib to MTH1. The adaptive biasing force (ABF) method was further employed to elucidate the unbinding process of (S)-crizotinib and (R)-crizotinib from the binding pocket of MTH1. ABF simulation results suggest that the reaction coordinates of the (S)-crizotinib from the binding pocket is different from (R)-crizotinib. The results from our study can reveal the details about the effect of chirality on the inhibition activity of crizotinib to MTH1 and provide valuable information for the design of more potent inhibitors. Public Library of Science 2015-12-17 /pmc/articles/PMC4683072/ /pubmed/26677850 http://dx.doi.org/10.1371/journal.pone.0145219 Text en © 2015 Niu et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Niu, Yuzhen Pan, Dabo Shi, Danfeng Bai, Qifeng Liu, Huanxiang Yao, Xiaojun Influence of Chirality of Crizotinib on Its MTH1 Protein Inhibitory Activity: Insight from Molecular Dynamics Simulations and Binding Free Energy Calculations |
title | Influence of Chirality of Crizotinib on Its MTH1 Protein Inhibitory Activity: Insight from Molecular Dynamics Simulations and Binding Free Energy Calculations |
title_full | Influence of Chirality of Crizotinib on Its MTH1 Protein Inhibitory Activity: Insight from Molecular Dynamics Simulations and Binding Free Energy Calculations |
title_fullStr | Influence of Chirality of Crizotinib on Its MTH1 Protein Inhibitory Activity: Insight from Molecular Dynamics Simulations and Binding Free Energy Calculations |
title_full_unstemmed | Influence of Chirality of Crizotinib on Its MTH1 Protein Inhibitory Activity: Insight from Molecular Dynamics Simulations and Binding Free Energy Calculations |
title_short | Influence of Chirality of Crizotinib on Its MTH1 Protein Inhibitory Activity: Insight from Molecular Dynamics Simulations and Binding Free Energy Calculations |
title_sort | influence of chirality of crizotinib on its mth1 protein inhibitory activity: insight from molecular dynamics simulations and binding free energy calculations |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683072/ https://www.ncbi.nlm.nih.gov/pubmed/26677850 http://dx.doi.org/10.1371/journal.pone.0145219 |
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