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: 1944733
• 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: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1944733
• 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 great than 30% of drugs. The beta-adrenoceptors (family A GPCRs), are key regulators of the cardiovascular and respiratory systems and well-established drug targets. beta1, beta2, and beta3 subtypes have distinct tissue distributions and pharmacological activity, but few known ligands show selectivity, making it difficult to research their distinct functions. We have recently identified, through advanced molecular modelling methods, a possible novel mode of binding of experimental subtype-selective ligands to 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 design, synthesise and pharmacologically characterise a library of ligands to test this hypothesis more rigorously. In parallel, molecular modelling studies will be performed that eventually will be correlated with pharmacological data.Objectives: -Design and synthesise a library of beta adrenoceptor ligands.-Characterise these ligands pharmacologically, using cell-based assays.-Use advanced molecular modelling methods, including flexible docking and molecular dynamics simulations, to predict the mode of binding of new beta adrenoceptor ligands to the proteins.-Make calculations of the binding affinities, and identify structure-activity relationships.Major methods:-Synthetic organic chemistry and structural elucidation.-Cell culture and pharmacological evaluation of ligand affinity and subtype selectivity.-Molecular modelling of ligand-protein complexes and analysis of structure-activity data.

gpcr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，超过30%的药物靶向它。-肾上腺素受体（A家族gpcr）是心血管和呼吸系统的关键调节因子，也是公认的药物靶点。Beta1， beta2和beta3亚型具有不同的组织分布和药理活性，但已知的配体很少有选择性，因此很难研究其不同的功能。我们最近通过先进的分子建模方法确定了实验亚型选择性配体与β肾上腺素受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设计、合成和药理学表征一个配体库，以更严格地验证这一假设。与此同时，分子模型研究将最终与药理学数据相关联。目的：-设计和合成β肾上腺素受体配体文库。-使用基于细胞的测定方法从药理学上表征这些配体。-使用先进的分子建模方法，包括灵活对接和分子动力学模拟，来预测新的β -肾上腺素能受体配体与蛋白质的结合模式。-计算结合亲和力，识别构效关系。主要方法：-合成有机化学和结构解析。-细胞培养和配体亲和力和亚型选择性的药理学评价。-配体-蛋白质复合物的分子建模和结构-活性数据分析。