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Hydrogen Bond Dynamic Propensity Studies for Protein Binding and Drug Design
We study the dynamic propensity of the backbone hydrogen bonds of the protein MDM2 (the natural regulator of the tumor suppressor p53) in order to determine its binding properties. This approach is fostered by the observation that certain backbone hydrogen bonds at the p53-binding site exhibit a dyn...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085089/ https://www.ncbi.nlm.nih.gov/pubmed/27792778 http://dx.doi.org/10.1371/journal.pone.0165767 |
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author | Menéndez, Cintia A. Accordino, Sebastián R. Gerbino, Darío C. Appignanesi, Gustavo A. |
author_facet | Menéndez, Cintia A. Accordino, Sebastián R. Gerbino, Darío C. Appignanesi, Gustavo A. |
author_sort | Menéndez, Cintia A. |
collection | PubMed |
description | We study the dynamic propensity of the backbone hydrogen bonds of the protein MDM2 (the natural regulator of the tumor suppressor p53) in order to determine its binding properties. This approach is fostered by the observation that certain backbone hydrogen bonds at the p53-binding site exhibit a dynamical propensity in simulations that differs markedly form their state-value (that is, formed/not formed) in the PDB structure of the apo protein. To this end, we conduct a series of hydrogen bond propensity calculations in different contexts: 1) computational alanine-scanning studies of the MDM2-p53 interface; 2) the formation of the complex of MDM2 with the disruptive small molecule Nutlin-3a (dissecting the contribution of the different molecular fragments) and 3) the binding of a series of small molecules (drugs) with different affinities for MDM2. Thus, the relevance of the hydrogen bond propensity analysis for protein binding studies and as a useful tool to complement existing methods for drug design and optimization will be made evident. |
format | Online Article Text |
id | pubmed-5085089 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-50850892016-11-04 Hydrogen Bond Dynamic Propensity Studies for Protein Binding and Drug Design Menéndez, Cintia A. Accordino, Sebastián R. Gerbino, Darío C. Appignanesi, Gustavo A. PLoS One Research Article We study the dynamic propensity of the backbone hydrogen bonds of the protein MDM2 (the natural regulator of the tumor suppressor p53) in order to determine its binding properties. This approach is fostered by the observation that certain backbone hydrogen bonds at the p53-binding site exhibit a dynamical propensity in simulations that differs markedly form their state-value (that is, formed/not formed) in the PDB structure of the apo protein. To this end, we conduct a series of hydrogen bond propensity calculations in different contexts: 1) computational alanine-scanning studies of the MDM2-p53 interface; 2) the formation of the complex of MDM2 with the disruptive small molecule Nutlin-3a (dissecting the contribution of the different molecular fragments) and 3) the binding of a series of small molecules (drugs) with different affinities for MDM2. Thus, the relevance of the hydrogen bond propensity analysis for protein binding studies and as a useful tool to complement existing methods for drug design and optimization will be made evident. Public Library of Science 2016-10-28 /pmc/articles/PMC5085089/ /pubmed/27792778 http://dx.doi.org/10.1371/journal.pone.0165767 Text en © 2016 Menéndez 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 (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Menéndez, Cintia A. Accordino, Sebastián R. Gerbino, Darío C. Appignanesi, Gustavo A. Hydrogen Bond Dynamic Propensity Studies for Protein Binding and Drug Design |
title | Hydrogen Bond Dynamic Propensity Studies for Protein Binding and Drug Design |
title_full | Hydrogen Bond Dynamic Propensity Studies for Protein Binding and Drug Design |
title_fullStr | Hydrogen Bond Dynamic Propensity Studies for Protein Binding and Drug Design |
title_full_unstemmed | Hydrogen Bond Dynamic Propensity Studies for Protein Binding and Drug Design |
title_short | Hydrogen Bond Dynamic Propensity Studies for Protein Binding and Drug Design |
title_sort | hydrogen bond dynamic propensity studies for protein binding and drug design |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085089/ https://www.ncbi.nlm.nih.gov/pubmed/27792778 http://dx.doi.org/10.1371/journal.pone.0165767 |
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