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

基于结构的 G 蛋白偶联受体变构配体发现

• 批准号: 8731953
• 负责人: Brian K Kobilka
• 金额: $ 124.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731953
• 关键词: Affinity; Alzheimer' s Disease; Behavior Disorders; Binding; Calcium ion; Cardiovascular Diseases; Cell Line; Chemicals; Cloning; Collaborations; Complementary DNA; Diabetes Mellitus; Disease; Dissection; Docking; Drug Targeting; Family; G-Protein-Coupled Receptors; Genes; Genetic Polymorphism; Glycoproteins; Goals; Hormones; Human Genome; Inflammation; Instruction; Libraries; Ligands; Lung diseases; Mediating; Medicine; Membrane Proteins; Methods; Mining; Nature; Neurotransmitters; Obesity; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Photons; Physiology; Property; Protons; Research Personnel; Roentgen Rays; Signal Transduction; Site; Specificity; Structure; Testing; Therapeutic; Translating; base; drug discovery; genome sequencing; high throughput screening; novel; novel strategies; programs; receptor; response; sensor; structural biology; success

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.

项目摘要（请参阅说明）： 该建议的总体目标是开发基于结构的方法，以发现具有新信号传导特性和特异性的新G蛋白偶联受体（GPCR）配体。 GPCR参与了几乎生理学的各个方面的调节，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，尽管这取得了成功，但它限制了该领域 到由规范的，通常是天然配体的先验地点。考虑到过去二十年来确定新的GPCR的出色进步，使用经典方法为该受体的药物发现令人失望。大多数可用的配体在正常部位作用，直接与天然激素和神经递质竞争。在极少数情况下，它们束缚了变构，他们 发现是偶然的，它们的优化很困难，他们的信号传导也是如此。 GPCR X射线结构的最新流出后，使用了施用配体对接方法，证明了这种方法可发现新型的直角配体化学型在几种GPCR中的可行性。我们提出了一个基于结构的GPCR的集成程序，以针对新的配体化学型，重点是变构配体，它们对新信号传导特性的测试，其结构与GPCR结合的确定以及对亲和力和信号的优化。在过去四年中，该提案建立在Kobilka，Shoichet，Suhichet，Sunahara和Gmeiner实验室中的现有合作网络上。这四个研究人员将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专业知识汇集在一起​​。 该组的初步研究证明了这种方法的可行性和潜在价值。