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: 8881224
• 负责人: Brian K Kobilka
• 金额: $ 123.97万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881224
• 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; 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; high throughput screening; human genome sequencing; individualized medicine; 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.

项目概述（见说明）：