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

DOI: 10.1021/acs.jpclett.6b01525 DOI Help

Authors: Yaw Sing Tan (Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR)) , Judith Reeks (Northern Institute for Cancer Research, Newcastle University) , Christopher J. Brown (p53 Laboratory, A*STAR) , Dawn Thean (p53 Laboratory, A*STAR) , Fernando Jose Ferrer Gago (p53 Laboratory, A*STAR) , Tsz Ying Yuen (Institute of Chemical & Engineering Sciences, A*STAR) , Eunice Tze Leng Goh (Singapore Eye Research Institute) , Xue Er Cheryl Lee (p53 Laboratory, A*STAR) , Claire E. Jennings (Newcastle University) , Thomas L. Joseph (Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR)) , Rajamani Lakshminarayanan (Singapore Eye Research Institute) , David P. Lane (p53 Laboratory, A*STAR) , Martin E. M. Noble (Northern Institute for Cancer Research, Newcastle University) , Chandra S. Verma (Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR); National University of Singapore; Nanyang Technological University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Journal Of Physical Chemistry Letters , VOL 7 , PAGES 3452 - 3457

State: Published (Approved)
Published: September 2016
Diamond Proposal Number(s): 9948

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.

Subject Areas: Chemistry


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography