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.

Bromophenols from Symphyocladia latiuscula Target Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases

“…Results from these functional assays demonstrated bromophenol 1 as a full D 3 R agonist and 3 as a full D 3 R/D 4 R agonist (order of agonist effect: D 4 R > D 3 R). From the docking study, bromophenols 1 – 3 were predicted to interact at OBS of D 3 R surrounded by the helices III, V, VI, and VII with Cys114, His345, Phe345, Phe346, Ser192, and Val189 . Likewise, for D 4 R binding, 1 – 3 were predicted to interact with Val193 and Ser197 in helix V and with Asp115 in helix III via H-bond interactions, which are crucial residues for drug binding to the receptor.…”

Rigorous Free Energy Simulations in Virtual Screening

“…Implicit solvent models have been proposed as one way to circumvent these latter problems, but implicit solvent models still suffer from the overlap issue and recent studies have shown that the neglect of explicit waters can lead to considerable artifacts. 89 At the time Zwanzig published his equation, there was no way to evaluate the ensemble average for a molecular system of interest. But by the mid-1980s, molecular dynamics and Monte Carlo methods and the evolution of computers made it possible to apply the equation to real systems, as first demonstrated in the laboratories of McCammon 90 and Jorgensen.…”

“…Explicit solvent also makes the sampling of protein domain motions difficult, due to water diffusion, which lengthens the time scale of such motions. Implicit solvent models have been proposed as one way to circumvent these latter problems, but implicit solvent models still suffer from the overlap issue and recent studies have shown that the neglect of explicit waters can lead to considerable artifacts …”

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…Destabilization of D3 inactive state(s) and flexibility of the ligands are among the elements that the most recent model available is proposing ( Ferraro et al., 2020 ). Molecular recognition steps, changes in hydration of the ligand binding pocket and ligand dependent receptor configuration changes are also important considerations for D2 and D3 in particular when docking flexible ligands and establishing comparisons ( Pal et al., 2019 ). Native system pharmacology studies are due to confirm the relevance of the observed in vitro differences.…”