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

G 蛋白偶联受体 (GPCR) 结合新模式的分子和计算机模拟研究

• 批准号: 2271315
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2271315
• 关键词: Molecular; silico; interrogation; novel; modes

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.

GPCR是存在于细胞膜中的重要信号转导蛋白，并且是许多稳态过程的必需调节剂，并且被>30%的药物靶向。该小组内的研究表明，传统的计算方法（基于已发表的X射线晶体结构模型）来合理化某些配体如何与其靶受体相互作用，并不能为实验观察到的活性提供有效的解释，或者无法合理地容纳这些配体在接受的结合位点。最近，我们已经确定，通过先进的分子模拟方法，一种可能的新模式的β-肾上腺素受体的配体结合。这种结合模式可以解释结构-活性关系数据，否则似乎矛盾。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。将进行分子建模研究，以研究这些潜在的新型结合模式，并将结果用于告知针对这些结合位点产生的新型配体的合成。然后将对新配体进行表征。基于我们对β-肾上腺素受体的研究，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。