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

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
Other Titles:
The Journal of Physical Chemistry Letters
Keywords:
Publication Date:
17 August 2016
Citation:
J. Phys. Chem. Lett. 2016, 7, 17, 3452-3457
Abstract:
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.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
We are grateful for funding from the A*STAR Joint Council Office. J.R. and C.E.J. are supported by grants from Astex Pharmaceuticals Ltd and Cancer Research UK (grant reference C240/A15751). We thank Diamond Light Source for access to beamlines I04 and I04-1 and Dr. Arnaud Basle for data collection.
Description:
ISSN:
1948-7185
Files uploaded:

File Size Format Action
779-acsjpclett6b01525.pdf 3.90 MB PDF Open