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Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design
[Image: see text] Protein flexibility poses a major challenge in binding site identification. Several computational pocket detection methods that utilize small-molecule probes in molecular dynamics (MD) simulations have been developed to address this issue. Although they have proven hugely successfu...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2016
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515508/ https://www.ncbi.nlm.nih.gov/pubmed/27532490 http://dx.doi.org/10.1021/acs.jpclett.6b01525 |
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author | Tan, Yaw Sing Reeks, Judith Brown, Christopher J. Thean, Dawn Ferrer Gago, Fernando Jose Yuen, Tsz Ying Goh, Eunice Tze Leng Lee, Xue Er Cheryl Jennings, Claire E. Joseph, Thomas L. Lakshminarayanan, Rajamani Lane, David P. Noble, Martin E. M. Verma, Chandra S. |
author_facet | Tan, Yaw Sing Reeks, Judith Brown, Christopher J. Thean, Dawn Ferrer Gago, Fernando Jose Yuen, Tsz Ying Goh, Eunice Tze Leng Lee, Xue Er Cheryl Jennings, Claire E. Joseph, Thomas L. Lakshminarayanan, Rajamani Lane, David P. Noble, Martin E. M. Verma, Chandra S. |
author_sort | Tan, Yaw Sing |
collection | PubMed |
description | [Image: see text] Protein flexibility poses a major challenge in binding site identification. Several computational pocket detection methods that utilize small-molecule probes in molecular dynamics (MD) simulations have been developed to address this issue. Although they have proven hugely successful at reproducing experimental structural data, their ability to predict new binding sites that are yet to be identified and characterized has not been demonstrated. Here, we report the use of benzenes as probe molecules in ligand-mapping MD (LMMD) simulations to predict the existence of two novel binding sites on the surface of the oncoprotein MDM2. One of them was serendipitously confirmed by biophysical assays and X-ray crystallography to be important for the binding of a new family of hydrocarbon stapled peptides that were specifically designed to target the other putative site. These results highlight the predictive power of LMMD and suggest that predictions derived from LMMD simulations can serve as a reliable basis for the identification of novel ligand binding sites in structure-based drug design. |
format | Online Article Text |
id | pubmed-5515508 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-55155082017-07-24 Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design Tan, Yaw Sing Reeks, Judith Brown, Christopher J. Thean, Dawn Ferrer Gago, Fernando Jose Yuen, Tsz Ying Goh, Eunice Tze Leng Lee, Xue Er Cheryl Jennings, Claire E. Joseph, Thomas L. Lakshminarayanan, Rajamani Lane, David P. Noble, Martin E. M. Verma, Chandra S. J Phys Chem Lett [Image: see text] Protein flexibility poses a major challenge in binding site identification. Several computational pocket detection methods that utilize small-molecule probes in molecular dynamics (MD) simulations have been developed to address this issue. Although they have proven hugely successful at reproducing experimental structural data, their ability to predict new binding sites that are yet to be identified and characterized has not been demonstrated. Here, we report the use of benzenes as probe molecules in ligand-mapping MD (LMMD) simulations to predict the existence of two novel binding sites on the surface of the oncoprotein MDM2. One of them was serendipitously confirmed by biophysical assays and X-ray crystallography to be important for the binding of a new family of hydrocarbon stapled peptides that were specifically designed to target the other putative site. These results highlight the predictive power of LMMD and suggest that predictions derived from LMMD simulations can serve as a reliable basis for the identification of novel ligand binding sites in structure-based drug design. American Chemical Society 2016-08-17 2016-09-01 /pmc/articles/PMC5515508/ /pubmed/27532490 http://dx.doi.org/10.1021/acs.jpclett.6b01525 Text en Copyright © 2016 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Tan, Yaw Sing Reeks, Judith Brown, Christopher J. Thean, Dawn Ferrer Gago, Fernando Jose Yuen, Tsz Ying Goh, Eunice Tze Leng Lee, Xue Er Cheryl Jennings, Claire E. Joseph, Thomas L. Lakshminarayanan, Rajamani Lane, David P. Noble, Martin E. M. Verma, Chandra S. Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design |
title | Benzene Probes in Molecular Dynamics Simulations Reveal
Novel Binding Sites for Ligand Design |
title_full | Benzene Probes in Molecular Dynamics Simulations Reveal
Novel Binding Sites for Ligand Design |
title_fullStr | Benzene Probes in Molecular Dynamics Simulations Reveal
Novel Binding Sites for Ligand Design |
title_full_unstemmed | Benzene Probes in Molecular Dynamics Simulations Reveal
Novel Binding Sites for Ligand Design |
title_short | Benzene Probes in Molecular Dynamics Simulations Reveal
Novel Binding Sites for Ligand Design |
title_sort | benzene probes in molecular dynamics simulations reveal
novel binding sites for ligand design |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515508/ https://www.ncbi.nlm.nih.gov/pubmed/27532490 http://dx.doi.org/10.1021/acs.jpclett.6b01525 |
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