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


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.

SUBMITTER: Pal RK 

PROVIDER: S-EPMC6768453 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Pal Rajat Kumar RK   Gadhiya Satishkumar S   Ramsey Steven S   Cordone Pierpaolo P   Wickstrom Lauren L   Harding Wayne W WW   Kurtzman Tom T   Gallicchio Emilio E  

PloS one 20190930 9


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  ...[more]

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