Molecular and in-silico interrogation of novel modes of binding at G protein-coupled receptors (GPCRs)

GPCRs是存在于细胞膜上的重要信号转导蛋白，是许多动态平衡过程的重要调节因子，30%的药物以GPCRs为靶标。该小组内部的研究表明，传统的计算方法(基于已发表的X射线晶体结构模型)合理化一些配体与其目标受体的相互作用方式，不能为实验观察到的活性提供有效的解释，或者无法明智地将这些配体容纳在可接受的结合部位。最近，我们通过先进的分子模拟方法，确定了一种可能的β-肾上腺素能受体上配体结合的新模式。这种结合模式可以解释原本看起来相互矛盾的结构-活性关系数据。了解这些典型的GPCRs如何与配体相互作用，可能与更广泛的GPCRs家族的其他成员高度相关。这个多学科项目的目的将是探索在其他GPCR家族成员中应用类似的新结合模式的可能性。将进行分子模拟研究，以研究这些潜在的新结合模式，以及用于为合成针对这些结合位点的新配体提供信息的结果。然后，将对新的配体进行药理学表征。在我们对β受体研究的基础上，这个以化学生物学为重点的项目将跨越合成化学、药理学和计算化学，以增加我们对配体与更广泛的GPCR家族成员相互作用的理解。

GPCRs are important signal transduction proteins residing in the cell membrane and are essential regulators of many homeostatic processes and targeted by >30% of drugs. Research within the group has demonstrated that traditional computational approaches (based on models of published x-ray crystal structures) to rationalise how some ligands interact with their target receptor do not offer a valid explanation for experimentally observed activity, or are unable to sensibly accommodate these ligands in the accepted binding site. We have recently identified, through advanced molecular modelling methods, a possible novel mode of binding for ligands at the beta-adrenoceptors. This mode of binding may explain structure-activity relationship data that otherwise appears contradictory. An understanding of how these prototypical GPCRs interact with ligands is likely to be highly relevant to other members of the wider GPCR family. The aim of this multidisciplinary project will be to explore the potential for similar novel binding modes across other GPCR family members. Molecular modelling studies will be performed that will investigate these potential novel binding modes, and the results used to inform the synthesis of novel ligands produced to target these binding sites. The novel ligands will then be pharmacologically characterised. Building on our research with the beta-adrenoceptors, this chemical biology-focused project will span the disciplines of synthetic chemistry, pharmacology and computational chemistry to increase our understanding of the way ligands interact with members of the wider family of GPCRs.