Induced polarization in drug-receptor binding: Contribution to the binding affinity of a meta-chlorobenzyl side chain in the S1 pocket of thrombin

MEDI 77

Menshawy Mohamed, mm323@buffalo.edu1, Bernhard Baum, bernhard.baum@staff.uni-marburg.de2, Marek Freindorf, mfrein@buffalo.edu3, Gerhard Klebe, klebe@staff.uni-marburg.de2, and David G. Hangauer, hangauer@acsu.buffalo.edu1. (1) Department of Chemistry, University at Buffalo, Natural Sciences Complex, Box 603000, Buffalo, NY 14260-3000, (2) Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, 35032, Germany, (3) Center for Computational Research, University at Buffalo, The State University of New York, Buffalo, NY 14260
Induced polarization of the electronic density in ligands by their protein receptors is a largely unexplored contributor to the drug-receptor binding processes. Other researchers have reported the surprisingly strong binding affinity of a meta-chlorobenzyl side chain in the anionic S1 pocket of thrombin and ascribed this to hydrophobic binding. We have designed and evaluated a series of meta-chlorobenzyl side chain analogs, and our data suggests that hydrophobic binding is not the reason for the surprisingly strong binding affinity of this side chain. The binding affinity of these analogs was evaluated by x-ray crystallography, ITC, quantum mechanical (QM) and combined quantum mechanical – molecular mechanical (QM/MM) calculations. The results of our study suggest that the unique polarization of the meta-chlorobenzyl side chain in the S1 pocket of the protein is a major contributor to its enhanced binding affinity.
 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007