Inclusion of enclosed hydration effects in the binding free energy estimation of dopamine D3 receptor complexes
Inclusion of enclosed hydration effects in the binding free energy estimation of dopamine D3 receptor complexes
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DOI：
10.1371/journal.pone.0222902
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发表时间：
2019-09-30
期刊：
影响因子：
3.7
通讯作者：
Gallicchio, Emilio
中科院分区：
文献类型：
--
作者：
Pal, Rajat Kumar;Gadhiya, Satishkumar;Gallicchio, Emilio
g蛋白偶联受体选择性拮抗剂的合理设计面临着局限水合作用和构象柔韧性的挑战。我们提出了一组c3取代(-)-stepholidine衍生物作为多巴胺D3受体的有效结合物。这些化合物的特征是生物化学的，以及通过计算机建模使用一种新的基于分子动力学的炼金术结合自由能方法，该方法结合了封闭水分子从结合位点位移的影响。采用显式溶剂化的水化位点分析法，得到了特定水化位点的自由位移能。这项工作强调了限制水合作用和构象重组在多巴胺受体分子识别机制中的关键作用，并说明了结合自由能模型代表这些关键现象的潜力。
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.