Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, Budapest, 1117, Hungary.
J Comput Aided Mol Des. 2019 Sep;33(9):787-797. doi: 10.1007/s10822-019-00224-w. Epub 2019 Sep 21.
Stabilizing unique receptor conformations, allosteric modulators of G-protein coupled receptors (GPCRs) might open novel treatment options due to their new pharmacological action, their enhanced specificity and selectivity in both binding and signaling. Ligand binding occurs at intrahelical allosteric sites and involves significant induced fit effects that include conformational changes in the local protein environment and water networks. Based on the analysis of available crystal structures of metabotropic glutamate receptor 5 (mGlu) we investigated these effects in the binding of mGlu receptor negative allosteric modulators. A large set of retrospective virtual screens revealed that the use of multiple protein structures and the inclusion of selected water molecules improves virtual screening performance compared to conventional docking strategies. The role of water molecules and protein flexibility in ligand binding can be taken into account efficiently by the proposed docking protocol that provided reasonable enrichment of true positives. This protocol is expected to be useful also for identifying intrahelical allosteric modulators for other GPCR targets.
稳定独特的受体构象，G 蛋白偶联受体 (GPCR) 的变构调节剂可能会因为它们新的药理作用、在结合和信号转导方面增强的特异性和选择性而开辟新的治疗选择。配体结合发生在螺旋内变构位点，并涉及显著的诱导契合效应，包括局部蛋白质环境和水网络的构象变化。基于对代谢型谷氨酸受体 5(mGlu)的现有晶体结构的分析，我们研究了这些效应在 mGlu 受体负变构调节剂结合中的作用。大量的回顾性虚拟筛选表明，与传统对接策略相比，使用多个蛋白质结构和包含选定的水分子可以提高虚拟筛选性能。所提出的对接方案可以有效地考虑水分子和蛋白质柔性在配体结合中的作用，为真正的阳性结果提供了合理的富集。该方案有望也可用于鉴定其他 GPCR 靶标中的螺旋内变构调节剂。
