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

描述（由申请人提供）：优化Eph亚型选择性拮抗剂作为神经系统Eph受体及其蛋白配体ephrin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，神经元发育，血管发生和病理性血管生成。Eph受体，尤其是A类，在发育和成人神经系统中都有作用。这项R21基金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）。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，采用基于结构的方法优化从HTS检测中获得的小分子先导物，以提高Eph受体结合亲和力和epa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，包括同源性建模、设计、合成和使用计算对接、直接结合和功能分析筛选重点文库。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新的作用机制的新疗法，用于治疗包括帕金森病和阿尔茨海默病在内的各种神经系统疾病。

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.