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

GPCRs是一种重要的信号转导蛋白，存在于细胞膜中，是许多稳态过程的重要调节因子，是大约30%的药物的靶标。该小组的研究表明，传统的计算方法（基于已发表的x射线晶体结构模型）来合理化一些配体如何与目标受体相互作用，并不能为实验观察到的活性提供有效的解释，或者不能在可接受的结合位点上合理地容纳这些配体。我们最近通过先进的分子建模方法确定了β -肾上腺素受体配体结合的一种可能的新模式。这种结合模式可以解释结构-活性关系数据，否则看起来是矛盾的。了解这些原型GPCR如何与配体相互作用可能与更广泛的GPCR家族的其他成员高度相关。这个多学科项目的目的是探索其他GPCR家族成员之间类似的新型结合模式的潜力。将进行分子模型研究，以调查这些潜在的新型结合模式，并将结果用于为合成针对这些结合位点产生的新型配体提供信息。这种新型配体随后将进行药理学表征。以我们对β -肾上腺素受体的研究为基础，这个以化学生物学为重点的项目将跨越合成化学、药理学和计算化学的学科，以增加我们对配体与更广泛的gpcr家族成员相互作用方式的理解。

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.