Optimization of EphA subtype-selective antagonists as probes for the nervous syst

EphA亚型选择性拮抗剂作为神经系统探针的优化

• 批准号: 7936819
• 负责人: LONGQIN HU
• 金额: $ 25.01万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7936819
• 关键词: 3-Dimensional; Adult; Affinity; Alzheimer' s Disease; Applications Grants; Arts; Binding; Binding Sites; Biochemical; Biological Assay; Complex; Crystallization; Development; Docking; Drug Design; Embryonic Development; Eph Family Receptors; EphA Receptors; EphA5 Receptor; Ephrins; Evaluation; Family; Goals; Gold; Growth Cones; Homology Modeling; Lead; Libraries; Ligand Binding; Ligands; Modeling; Molecular; Nervous system structure; Parkinson Disease; Pathologic Neovascularization; Pathologic Processes; Physiological; Play; Process; Proteins; Receptor Protein-Tyrosine Kinases; Roentgen Rays; Role; Screening procedure; Solutions; Structure; Techniques; Therapeutic Agents; Tyrosine; analog; base; chemical synthesis; design; high throughput screening; inhibitor/antagonist; model design; nervous system disorder; neuron development; novel therapeutics; programs; public health relevance; receptor; receptor binding; receptor function; response; small molecule; small molecule libraries; vasculogenesis

DESCRIPTION (provided by applicant): Optimization of EphA subtype-selective antagonists as probes for the nervous system Eph receptors and their protein ligand ephrins play important roles in many different physiological and pathophysiological processes including embryogenesis, neuronal development, vasculogenesis, and pathological angiogenesis. Eph receptors, especially the A class, have been implicated in both the developing and adult nervous system. The goal of this R21 grant application is to optimize small molecule EphA subtype- selective antagonists as probes for the nervous system in response to RFA-NS-09-003: Optimization of Small Molecule Probes for the Nervous System (R21). An interdisciplinary team of experts including a medicinal chemist, two molecular biologists, a structure biologist, and a computational chemist is assembled to take a structure-based approach to optimize small molecule leads obtained from HTS assays to increase Eph receptor binding affinity and EphA subtype-selectivity. A variety of state-of-the-art drug design principles, biochemical and biophysical techniques will be used in this project including homology modeling, design, synthesis, and screening of focused libraries using both computational docking, direct binding and functional assays. The small molecule antagonists optimized will help further elucidate the EphA-ephrin-A interactions in the nervous system and could lead to the development of novel therapeutics with new mechanisms of action for a variety of nervous system disorders including Parkinson's and Alzheimer's disease. PUBLIC HEALTH RELEVANCE: High affinity EphA receptor-specific antagonists developed in this project can be used as pharmacological probes for the elucidation of ephrin-A and EphA receptor function in various physiological and pathological processes in the nervous system. They could lead to the development of novel therapeutic agents for nervous system disorders including Parkinson's and Alzheimer's disease.

描述（由申请人提供）：作为神经系统Eph受体及其蛋白配体肝配蛋白的探针的EphA亚型选择性拮抗剂的优化在许多不同的生理和病理生理过程中起重要作用，包括胚胎发生、神经元发育、血管发生和病理性血管生成。Eph受体，特别是A类，在发育和成人神经系统中都有涉及。该R21授权申请的目标是优化小分子EphA亚型选择性拮抗剂作为神经系统的探针，以响应RFA-NS-09-003：神经系统小分子探针的优化（R21）。一个跨学科的专家团队，包括一名药物化学家，两名分子生物学家，一名结构生物学家和一名计算化学家，组装采取基于结构的方法来优化从HTS测定获得的小分子引线，以增加Eph受体结合亲和力和EphA亚型选择性。各种国家的最先进的药物设计原则，生物化学和生物物理技术将被用于这个项目，包括同源建模，设计，合成，并使用计算对接，直接结合和功能分析的重点库筛选。优化的小分子拮抗剂将有助于进一步阐明EphA-ephrin-A在神经系统中的相互作用，并可能导致开发具有用于各种神经系统疾病（包括帕金森病和阿尔茨海默病）的新作用机制的新型治疗剂。 公共卫生相关性：本项目开发的高亲和力EphA受体特异性拮抗剂可用作药理学探针，用于阐明ephrin-A和EphA受体在神经系统各种生理和病理过程中的功能。它们可能导致神经系统疾病（包括帕金森病和阿尔茨海默病）的新型治疗药物的开发。