Medicinal Chemistry

药物化学

• 批准号: 9302484
• 负责人: Peter Gmeiner
• 金额: $ 14.18万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302484
• 关键词: ADRB2 gene; Active Sites; Address; Adopted; Adrenergic Receptor; Affinity; Agonist; Allosteric Regulation; Allosteric Site; Alprenolol; Binding; Binding Sites; Biological; Biological Assay; Biophysics; Chemicals; Collaborations; Complement; Crystallization; Development; Diffuse; Dissociation; Docking; Entropy; Family; G-Protein-Coupled Receptors; Genes; Goals; Human; Instruction; Investigation; Iodine; Ions; Kinetics; Label; Lead; Libraries; Ligand Binding; Ligands; Ligation; Modification; Molecular; Molecular Conformation; Movement; Muscarinic Acetylcholine Receptor; Muscarinic M2 Receptor; Muscarinic M3 Receptor; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Positioning Attribute; Preparation; Process; Property; Proteins; Reagent; Resolution; Salmeterol; Signal Pathway; Signal Transduction; Solubility; Structure; Sulfides; Testing; Therapeutic; Variant; Work; analog; base; carboxylate; design; dithiol; drug discovery; electron density; enantiomer; experimental study; fluorophore; functional group; improved; innovation; insight; novel; pharmacophore; physical property; positive allosteric modulator; programs; receptor; receptor binding; scaffold; screening; tool; urinary gonadotropin fragment

PROJECT SUMMARY (See instructions); G-protein coupled receptors (GPCRs) comprise a large superfamily of target proteins (nearly 800 different human genes encode for GPCRs) and each of them can adopt functionally distinct conformations. New chemotypes and allosteric modulation, which are the focus of this project, will facilitate the development of novel, highly selective drugs because allosteric sites are significantly less conserved between GPCR subtypes and closely related sub-families and display higher structural variation. The Medicinal Chemistry Core will synthesize new GPCR ligands as reagents to enable new crystal structures, as molecular tools to help deconvolute signaling pathways, and as innovative lead compounds. This core aims to provide such optimized molecules, working intimately with all three ofthe Projects. Collaborating with Project 3, the working plan ofthe Medicinal Chemistry Core includes the development of covalent agonists to facilitate high-resolution, active state structures ofthe M2 and MS muscarinic receptors and the synthesis of heavy atom-substituted ligands for structures of muscarinic receptors bound to allosteric modulators. To evaluate effect of allosteric ligands on binding kinetics of purified GPCRs (Project 2), fluorophore-labeled M2 and MS receptor antagonist and agonists will be developed. In the field of ligand discovery and optimization, the Medicinal Chemistry Core will work intimately with Project 1 to optimize new chemotypes identified from library docking campaigns and to develop high affinity allosteric ligands from docking hits, which must be improved by at least two order of magnitude in affinity to become valuable tools and lead compounds for drug discovery. The Medicinal Chemistry Core essentially contributes to the larger project�combining GPCR crystal structure determination with sophisticated new biophysical assays with molecular docking campaigns for new chemotypes.

项目摘要（参见说明）；G 蛋白偶联受体 (GPCR) 包含一个大的靶蛋白超家族（近 800 个不同的人类基因编码 GPCR），并且它们中的每一个都可以采用功能上不同的构象和变构调节。该项目的重点将促进新型、高选择性药物的开发，因为 GPCR 亚型和密切相关的亚家族之间的变构位点显着较少保守，并且显示出更高的结构药物化学核心将合成新的 GPCR 配体作为试剂以实现新的晶体结构，作为帮助解旋信号通路的分子工具，以及作为创新的先导化合物，该核心旨在提供此类优化的分子，与所有三个药物密切合作。项目 与项目 3 合作，药物化学核心的工作计划包括开发共价激动剂，以促进 M2 和 MS 毒蕈碱受体的高分辨率、活性状态结构和合成与变构调节剂结合的毒蕈碱受体结构的重原子取代配体 为了评估变构配体对纯化 GPCR 结合动力学的影响（项目 2），将开发荧光团标记的 M2 和 MS 受体拮抗剂和激动剂。在配体发现和优化领域，药物化学核心将与项目 1 密切合作，优化从库对接活动中识别出的新化学型，并开发来自对接命中的高亲和力变构配体，其亲和力必须提高至少两个数量级才能成为药物发现的有价值的工具和先导化合物，药物化学核心本质上有助于更大的项目——将 GPCR 晶体结构测定与复杂的相结合。新的生物物理测定与新化学型的分子对接活动。