Structure-based discovery of allosteric ligands for G Protein Coupled Receptors

项目总结（见说明）： 该提案的总体目标是开发基于结构的方法来发现具有新的信号传导特性和特异性的新的G蛋白偶联受体（GPCR）配体。GPCR参与调节生理学的几乎每个方面，并且是药物发现的关键靶标。到目前为止，GPCR的配体发现工作一直是经验驱动的，尽管这已经取得了成功，但它限制了该领域 通常是天然配体的位置。考虑到在过去二十年中在鉴定新的GPCR方面的显著进展，使用经典方法对该受体家族的药物发现一直令人失望。大多数可用的配体作用于正构位点，直接与天然激素和神经递质竞争。在罕见的情况下，他们的结合变构， 发现是偶然的，它们的优化是困难的，就像它们的信号分解一样。 最近的风化GPCR X-射线结构其次是应用配体对接方法，证明了这种方法的可行性，为几个GPCR的新的正构配体化学型的发现。我们提出了一个基于结构的开发新的配体化学型的GPCR的集成程序，重点是变构配体，它们的测试新的信号传导特性，确定它们的结构结合到它们的GPCR，以及它们的亲和力和信号传导的优化。该提案建立在过去四年Kobilka，Shoichet，Sunahara和Gmeiner实验室之间现有合作网络的基础上。这四位研究人员汇集了GPCR结构生物学，配体对接，GPCR药理学和功能以及药物化学方面的独特专业知识。 该小组的初步研究证明了这种方法的可行性和潜在价值。

PROJECT SUMMARY (See instructions): The overall goal of this proposal it to develop structure-based approaches to discover new G protein coupled receptor (GPCR) ligands having new signaling properties and specificities. GPCRs are involved in regulating virtually every aspect of physiology and are pivotal targets for drug discovery. Until now, ligand discovery efforts for GPCR has been empirically driven, and though this has had successes, it has restricted the field to sites precedented by canonical, often natural ligands. Considering the remarkable progress in identifying new GPCRs over the past two decades, drug discovery for this family of receptors using classical approaches has been disappointing. Most available ligands act at orthosteric sites, competing directly with the natural hormones and neurotransmitters. In the rare circumstances that they bind allosterically, their discovery has been fortuitous, their optimization difficult, as has been the dissection of their signaling. The recent efflorescence of GPCR X-ray structures was followed by the application ligand docking methods demonstrating the feasibility of this approach for the discovery of novel orthosteric ligand chemotypes for several GPCRs. We propose an integrated program of structure-based exploitation of GPCRs for new ligand chemotypes with an emphasis on allosteric ligands, their testing for new signaling properties, the determination of their structures bound to their GPCRs, and their optimization for affinity and signaling. This proposal builds on a network of existing collaborations among the labs of Kobilka, Shoichet, Sunahara and Gmeiner over the past four years. These four investigators bring together a unique combination of expertise in GPCR structural biology, ligand docking, GPCR pharmacology and function, and medicinal chemistry. Preliminary studies from this group demonstrate the feasibility and potential value of this approach.