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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...

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Detalles Bibliográficos
Autores principales: Tiwary, Pratyush, Mondal, Jagannath, Berne, B. J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2017
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.
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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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