AMPA受体非竞争性拮抗剂的虚拟筛选及相互作用机理研究

项目名称： AMPA受体非竞争性拮抗剂的虚拟筛选及相互作用机理研究

项目编号： No.31300599

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 杜娟

作者单位： 青岛农业大学

项目金额： 22万元

中文摘要： AMPAR受体（AMPARs）在中枢神经系统中介导大部分快速兴奋性神经传递。过度激活的AMPARs可引起神经元损伤，与多种神经性损伤及慢性神经退行性疾病有关，例如脑缺血、癫痫、帕金森、阿兹海默症等。AMPARs非竞争性拮抗剂可以抑制该受体离子通道打开，具有神经保护作用，因此成为较有潜力的治疗神经系统疾病的药物研发对象。这类拮抗剂如何与AMPARs 结合以及怎样发挥抑制功能的机理尚不明确。本项目拟在前期研究的基础上，以阐明非竞争性拮抗剂作用机理为目标，利用分子对接、动力学模拟等方法研究AMPARs 非竞争性拮抗剂与受体之间的相互作用模式，探讨这类拮抗剂发挥变构调节功能的结构因素；另外利用药效团模型、分子对接、结合自由能计算等方法进行数据库虚拟筛选，拟得到具有结构多样性的高活性的AMPARs非竞争性拮抗剂，为开发治疗神经系统疾病的创新药物奠定基础。

中文关键词： AMPA受体；非竞争性拮抗剂；分子动力学模拟；虚拟筛选；

英文摘要： α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) mediate majority fast excitatory neurotransmission in the central nervous system. AMPARs over-activation induces neuronal cell death, implicated in various neurological diseases, such as cerebral ischaemia, epilepsy, Parkinson's, and Alzheimer's disease, etc. The noncompetitive antagonists can inhibit channel gating and have neuroprotective effects, thus became potential candidates for treatment of neurological disease. How these antagonists bind with AMPARs and exert inhibition mechanism remains unclear. In this project, we will investigate the interaction mode between noncompetitive antagonists and AMPARs using molecular docking and molecular dynamics simulation. We try to elucidate the allosteric modulation mechanism of these antagonist. Further, pharmacophore model, molecular docking and binding free energy calculation will be used to screen database for obtaining novel AMPARs noncompetitive antagonists with various structural skeletons and high antagonist activities. This project will provide new entities for development of novel drugs for treatment of neurological disease.

英文关键词： AMPA receptor；non-competitive antagonist；molecular synamics simulation；virtual screening；