新型A2A受体拮抗剂的药物设计和抗PD活性研究

项目名称： 新型A2A受体拮抗剂的药物设计和抗PD活性研究

项目编号： No.81502982

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 田盛

作者单位： 苏州大学

项目金额： 18.5万元

中文摘要： 帕金森病是一种以静止性震颤、运动迟缓、肌强直为主要临床表现的神经系统退行性疾病。以多巴胺受体激动剂和左旋多巴为代表的用于治疗帕金森病的药物对于帕金森病症状的缓解有着一定的疗效，但是其并不能阻止病情的进一步发展且长时间使用还存在着疗效减退和运动障碍等副作用。在以调节非多巴胺体系用于治疗帕金森病的治疗策略中，腺苷A2A受体拮抗剂已显示出较大的研发潜力。申请人利用虚拟筛选结合活性实验测试已成功发现了多类全新结构且具有较高活性和专一性的A2A受体小分子拮抗剂。本研究项目拟在申请人前期研究的基础上，充分考虑A2A受体蛋白柔性对虚拟筛选结果的影响，采用机器学习方法构建基于分子对接和复合物结构药效团模型的多构象整合虚拟筛选模型，并利用该预测模型，结合分子动力学模拟、结合自由能计算以及体内外活性测试发现活性好、专一性强、结构新颖的理想A2A受体小分子拮抗剂，为下一步抗PD药物的开发奠定坚实的基础。

中文关键词： 帕金森病；腺苷A2A受体拮抗剂；虚拟筛选；蛋白柔性；机器学习

英文摘要： Parkinson’s disease (PD) is a neurodegenerative disease characterized by the static tremor, bradykinesia and rigidity. The representative therapies, such as dopamine agonists and L-Dopa for treating PD, can provide symptomatic relief without slowing or stopping the disease progression, and long-term usage of these drugs is associated with diminished efficacy and motor fluctuation etc. Among the nondopaminergic strategies for the treatment of Parkinson’s disease, antagonists of adenosine A2A receptor has emerged to show great potential. The applicant have identified several promising A2A receptor antagonists with good activity, high selectivity, multiclass and novel chemical structures by using molecular docking-based virtual screening and biological activities testing. Based on the previous studies and taking the influences of protein flexibility for A2A receptor on the virtual screening into a full consideration, the project plans to build a parallel virtual screening strategy based on multiple receptor conformations by integrating the predictions from molecular docking and complex-based pharmacophore modeling by using machine-learning approaches. The well-validated integrated screening model is applied to screen larger compound libraries. The promising compounds are submitted to molecular dynamics simulations and binding free energy calculations. According to the results of binding free energy calculations and structural clustering, some potential A2A receptor antagonists will be chosen for biological and anti-Parkinson’s disease activities testing. The goal of the project is to identify promising A2A receptor antagonists with good activity, high selectivity and novel scaffolds, aiming at the development of new drugs for combating anti-Parkinson’s disease.

英文关键词： Parkinson’s disease;adenosine A2A receptor antagonist;virtual screening;protein flexibility;machine learning