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Lookup NU author(s): Dr Judith Reeks, Dr Claire Jennings, Professor Martin NobleORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Tan YS, Reeks J, Brown CJ, Thean D, Gago FJF, Yuen TY, Goh ETL, Lee XEC, Jennings CE, Joseph TL, Lakshminarayanan R, Lane DP, Noble MEM, Verma CS
Publication type: Article
Publication status: Published
Journal: Journal of Physical Chemistry Letters
Year: 2016
Volume: 7
Issue: 17
Pages: 3452-3457
Print publication date: 01/09/2016
Online publication date: 17/08/2016
Acceptance date: 17/08/2016
Date deposited: 04/11/2016
ISSN (electronic): 1948-7185
Publisher: American Chemical Society
URL: http://dx.doi.org/10.1021/acs.jpclett.6b01525
DOI: 10.1021/acs.jpclett.6b01525
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