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: 8550870
• 负责人: Brian K Kobilka
• 金额: $ 131.49万
• 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/8550870
• 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（参见说明）： 该提案的总体目标是开发基于结构的方法来发现具有新信号传导特性和特异性的新 G 蛋白偶联受体 (GPCR) 配体。 GPCR 几乎参与调节生理学的各个方面，并且是药物发现的关键目标。到目前为止，GPCR 的配体发现工作一直是凭经验驱动的，尽管这已经取得了成功，但它限制了该领域 到前面有规范的、通常是天然配体的位点。考虑到过去二十年在识别新 GPCR 方面取得的显着进展，使用经典方法发现该受体家族的药物却令人失望。大多数可用的配体作用于正位点，直接与天然激素和神经递质竞争。在极少数情况下，它们以变构方式结合，它们的 发现是偶然的，它们的优化很困难，对其信号传导的剖析也是如此。 最近 GPCR X 射线结构的繁荣随后出现了配体对接方法的应用，证明了这种方法对于发现几种 G​​PCR 的新型正位配体化学型的可行性。我们提出了一个基于结构的 GPCR 开发新配体化学型的综合计划，重点是变构配体、新信号传导特性的测试、与其 GPCR 结合的结构的确定以及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。