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How and when does an anticancer drug leave its binding site?
Obtaining atomistic resolution of drug unbinding from a protein is a much sought-after experimental and computational challenge. We report the unbinding dynamics of the anticancer drug dasatinib from c-Src kinase in full atomistic resolution using enhanced sampling molecular dynamics simulations. We...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451192/ https://www.ncbi.nlm.nih.gov/pubmed/28580424 http://dx.doi.org/10.1126/sciadv.1700014 |
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author | Tiwary, Pratyush Mondal, Jagannath Berne, B. J. |
author_facet | Tiwary, Pratyush Mondal, Jagannath Berne, B. J. |
author_sort | Tiwary, Pratyush |
collection | PubMed |
description | Obtaining atomistic resolution of drug unbinding from a protein is a much sought-after experimental and computational challenge. We report the unbinding dynamics of the anticancer drug dasatinib from c-Src kinase in full atomistic resolution using enhanced sampling molecular dynamics simulations. We obtain multiple unbinding trajectories and determine a residence time in agreement with experiments. We observe coupled protein-water movement through multiple metastable intermediates. The water molecules form a hydrogen bond bridge, elongating a specific, evolutionarily preserved salt bridge and enabling conformation changes essential to ligand unbinding. This water insertion in the salt bridge acts as a molecular switch that controls unbinding. Our findings provide a mechanistic rationale for why it might be difficult to engineer drugs targeting certain specific c-Src kinase conformations to have longer residence times. |
format | Online Article Text |
id | pubmed-5451192 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54511922017-06-02 How and when does an anticancer drug leave its binding site? Tiwary, Pratyush Mondal, Jagannath Berne, B. J. Sci Adv Research Articles Obtaining atomistic resolution of drug unbinding from a protein is a much sought-after experimental and computational challenge. We report the unbinding dynamics of the anticancer drug dasatinib from c-Src kinase in full atomistic resolution using enhanced sampling molecular dynamics simulations. We obtain multiple unbinding trajectories and determine a residence time in agreement with experiments. We observe coupled protein-water movement through multiple metastable intermediates. The water molecules form a hydrogen bond bridge, elongating a specific, evolutionarily preserved salt bridge and enabling conformation changes essential to ligand unbinding. This water insertion in the salt bridge acts as a molecular switch that controls unbinding. Our findings provide a mechanistic rationale for why it might be difficult to engineer drugs targeting certain specific c-Src kinase conformations to have longer residence times. American Association for the Advancement of Science 2017-05-31 /pmc/articles/PMC5451192/ /pubmed/28580424 http://dx.doi.org/10.1126/sciadv.1700014 Text en Copyright © 2017, The Authors http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (http://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Tiwary, Pratyush Mondal, Jagannath Berne, B. J. How and when does an anticancer drug leave its binding site? |
title | How and when does an anticancer drug leave its binding site? |
title_full | How and when does an anticancer drug leave its binding site? |
title_fullStr | How and when does an anticancer drug leave its binding site? |
title_full_unstemmed | How and when does an anticancer drug leave its binding site? |
title_short | How and when does an anticancer drug leave its binding site? |
title_sort | how and when does an anticancer drug leave its binding site? |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451192/ https://www.ncbi.nlm.nih.gov/pubmed/28580424 http://dx.doi.org/10.1126/sciadv.1700014 |
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