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posted Sep 7, 2016, 6:20 AM by Emilio Gallicchio   [ updated Sep 7, 2016, 6:24 AM ]
We are happy to announce that a team of CUNY investigators led by our laboratory and including Prof. Lauren Wickstrom (Borough of Manhattan Community College), Prof. Tom Kurtzman (Lehman College), and Prof. Wayne Harding (Hunter College) has been awarded a 1-year Interdisciplinary Research Grant award of $39,500 by the CUNY Office of Research to conduct theoretical and experimental studies of the inhibition of the D3 dopamine receptor:

A Combined Treatment of Hydration and Dynamical Effects for the Modeling of Protein-Ligand Binding Thermodynamics

Summary. The project seeks to develop an improved computational protocol for the study of protein-drug interactions marrying the accuracy of detailed explicit solvation models with the versatility of implicit solvation approaches, and to validate it experimentally on the important D3 dopamine receptor drug target. The work will lead to improved descriptions of the displacement of water molecules from the protein surface and of the dynamical response of molecular conformations upon binding. Current computer models of molecular binding lack in one or both of these critical elements. The primary aim of the project is to exploit the unique and complementary expertise of our team of investigators at CUNY to establish a proof-of-concept base and acquire sufficient preliminary data to compete for federal funding at the national level.

The team will work to develop a custom parameterization of the AGBNP solvation model for the D3 dopamine receptor using accurate Hydration Site Analysis data obtained from explicit solvent simulations. The resulting model will be employed to predict binding constants of a virtual library of D3 inhibitors using the BEDAM alchemical methodology. The most promising identified inhibitors will be synthesized and essayed for binding.  Selective inhibition of the dopamine D3 receptor is a promising therapeutic approach for the treatment of drug abuse disorders. Building on the methodology employed in our recent participation to the SAMPL5 blinded challenge, the project will for the first time attempt to apply a model combining enclosed hydration effects and a dynamical description of binding to a complex protein receptor system.

The award will help fund the research of Rajat Pal, a Ph.D. student in our lab, for the next year. Thanks!