Modeling and docking to de-orphanize the GPCRome

 描述(申请人提供)：拟议的研究将对350个内源性配体未知的非嗅觉G蛋白偶联受体(GPCRs)中的大约100个应用比较建模和通过分子对接发现配体。GPCRs由于其在细胞信号传递中的中心地位而成为引人注目的药物靶点；作为一类，它们能够结合从质子和金属离子到小分子和脂类到多肽、激素甚至折叠的球状蛋白等极其多样化的化学配体。尽管有这种多样性，GPCRs共享一个保守的作用机制，通过这种保守的作用机制，特征构象变化通过细胞膜传递信息来激活细胞内信号通路。众所周知，GPCR胞外结合位点具有高度的“可药性”--也就是接受外源小分子的相互作用--事实上，它们代表了目前市场上30%至50%的药物的蛋白质靶标。因此，所谓的“孤儿”GPCRs没有注释的内源性配体，为未来的药物开发提供了丰富的新作用机制。从历史上看，GPCRs一直是一种新的方法，该项目将首先利用经实验确定的具有代表性的孤儿GPCRs的配体，使用已证明会导致高命中率的方法，在大型化合物数据库上进行虚拟筛选。接下来，这一初始阶段的结果将用于改进和自动化方法，以构建一个可应用于孤立的GPC罗马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，目的不仅是确定作为工具化合物的“替代配体”，而且还确定每个GPCR的内源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.