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

Autoři: Rajat Kumar Pal aff001;  Satishkumar Gadhiya aff003;  Steven Ramsey aff002;  Pierpaolo Cordone aff002;  Lauren Wickstrom aff006;  Wayne W. Harding aff002;  Tom Kurtzman aff002;  Emilio Gallicchio aff001
Působiště autorů: Department of Chemistry, Brooklyn College, 2900 Bedford Avenue, Brooklyn, NY 11210, United States of America aff001;  PhD Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY 10016, United States of America aff002;  PhD Program in Chemistry, The Graduate Center of the City University of New York, New York, NY 10016, United States of America aff003;  Department of Chemistry, Hunter College, 695 Park Avenue, NY 10065, United States of America aff004;  Department of Chemistry, Lehman College, 250 Bedford Park Blvd. West, Bronx, NY 10468, United States of America aff005;  Department of Science, Borough of Manhattan Community College, 199 Chambers Street, New York, NY 10007, United States of America aff006
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222902


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.

Klíčová slova:

Binding analysis – Crystal structure – Dopamine – Free energy – Thermodynamics – Solvation – Receptor physiology – Receptor binding assays


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