Inclusion of enclosed hydration effects in the binding free energy estimation of dopamine D3 receptor complexes

Authors

Rajat Kumar Pal, CUNY Brooklyn College
Satishkumar Gadhiya, CUNY Hunter College
Steven Ramsey, CUNY Lehman CollegeFollow
Pierpaolo Cordone, CUNY Hunter College
Lauren Wickstrom, CUNY Borough of Manhattan Community College
Wayne W. Harding, CUNY Graduate Center
Tom Kurtzman, CUNY Lehman CollegeFollow
Emilio Gallicchio, CUNY Brooklyn College

Document Type

Article

Publication Date

9-30-2019

Abstract

Confined hydration and conformational flexibility are some of the challenges encountered for the rational design of selective antagonists of G-protein coupled receptors.We present a set of C3-substituted (-) -stepholidine derivatives as potent binders of the dopamine D3 receptor.The compounds are characterized biochemically, as well as by computer modeling using a novel molecular dynamics-based alchemical binding free energy approach which incorporates the effect of the displacement of enclosed water molecules from the binding site.The free energy of displacement of specific hydration sites is obtained using the Hydration Site Analysis method with explicit solvation. This work underscores the critical role of confined hydration and conformational reorganization in the molecular recognition mechanism of dopamine receptors and illustrates the potential of binding free energy models to represent these key phenomena.

Comments

This work was originally published in PLOS ONE, available at https://doi.org/10.1371/journal.pone.0222902

This article is distributed under the terms and conditions of the Creative Commons Attribution (CC BY) License (https://creativecommons.org/licenses/by/4.0/).