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

描述(申请人提供)：优选EphA亚型选择性拮抗剂作为神经系统Eph受体及其蛋白配体ephins的探针，在许多不同的生理和病理生理过程中发挥重要作用，包括胚胎发生、神经发育、血管生成和病理性血管生成。Eph受体，特别是A类受体，与发育中的神经系统和成人神经系统都有关系。这项R21拨款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探针，以响应RFA-NS-09-003：优化神经系统小分子探针(R21)。一个由一名药物化学家、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成的跨学科专家团队被聚集在一起，采取基于结构的方法来优化从HTS分析中获得的小分子线索，以提高Eph受体结合亲和力和EphA亚型选择性。该项目将使用各种最先进的药物设计原则、生化和生物物理技术，包括使用计算对接、直接结合和功能分析对焦点文库进行同源建模、设计、合成和筛选。经过优化的小分子拮抗剂将有助于进一步阐明神经系统中EphA-ePhin-A的相互作用，并可能导致开发具有新作用机制的新疗法，用于治疗包括帕金森氏症和阿尔茨海默病在内的各种神经系统疾病。 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探针，阐明Ephin-A和EphA受体在神经系统各种生理和病理过程中的功能。它们可能会导致开发出治疗包括帕金森氏症和阿尔茨海默病在内的神经系统疾病的新型治疗剂。

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.