Modeling and docking to de-orphanize the GPCRome

 描述（由申请人提供）：拟议的研究将通过分子对接将比较建模和配体发现应用于350种非嗅觉G蛋白偶联受体（GPCR）中的约100种，这些受体的内源性配体未知。GPCR是引人注目的药物靶点，因为它们在细胞信号传导中的中心位置;作为一类，它们能够结合极其化学多样的配体，从质子和金属离子到小分子和脂质到肽激素甚至折叠的球状蛋白。尽管存在这种多样性，但GPCR具有保守的作用机制，通过该机制，特征性构象变化将信息传递到细胞膜上以激活细胞内信号传导途径。GPCR胞外结合位点以高度“可药物化”而闻名--也就是说，接受外源性小分子的相互作用--事实上，它们代表了目前市场上30%至50%药物的蛋白质靶点。因此，没有注释的内源性配体的所谓“孤儿”GPCR代表了用于未来药物开发的新作用机制的丰富来源。从历史上看，GPCR一直是该项目的开始，利用实验鉴定的代表性孤儿GPCR的配体，使用已显示出高命中率的方法对大型化合物数据库进行虚拟筛选。接下来，这个初始阶段的结果将用于改进和自动化方法，以构建可以在孤立GPCRome上应用的集成建模和对接管道。此外，将使用化学信息学、对接和蛋白质-蛋白质界面分析，目的不仅是鉴定可用作工具化合物的“替代配体”，而且是鉴定每个GPCR的内源性配体及其在代谢组中的作用。

 DESCRIPTION (provided by applicant): The proposed research will apply comparative modeling and ligand discovery by molecular docking to the approximately 100 out of 350 non-olfactory G-protein coupled receptors (GPCRs) for which endogenous ligands are not known. GPCRs are compelling drug targets due to their central position in cellular signaling; as a class, they are capable of binding extremely chemically diverse ligands ranging from protons and metal ions to small molecules and lipids to peptides hormones and even folded globular proteins. Despite this diversity, GPCRs share a conserved mechanism of action by which characteristic conformational changes transduce information across the cell membrane to activate intracellular signaling pathways. GPCR extracellular binding sites are known for being highly "druggable"-that is, receptive to interactions by exogenous small molecules-and in fact they represent the protein targets of between 30% and 50% of drugs currently on the market. The so-called "orphan" GPCRs, with no annotated endogenous ligands, therefore represent a rich source of novel mechanisms of action for future drug development. Historically, GPCRs have been This project will begin by leveraging experimentally identified ligands of representative orphan GPCRs to perform virtual screening on a large compound database using a methodology already shown to result in high hit rates. Next, the results of this initial phase wil be used to refine and automate the methodology to construct an integrated modeling and docking pipeline that could be applied across the orphan GPCRome. Additionally, chemoinformatics, docking, and protein-protein interface analysis will be used with the goal of identifying not only "surrogate ligands" useful as tool compounds, but also the endogenous ligands of each GPCR and their role in the metabolome.