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Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design

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.

Publication metadata

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


DOI: 10.1021/acs.jpclett.6b01525


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Funder referenceFunder name
A*STAR Joint Council Office
Astex Pharmaceuticals Ltd
C240/A15751Cancer Research UK