基于结核杆菌代谢关键酶DprE1结构的新型抗结核药物筛选、设计和活性评价

项目名称： 基于结核杆菌代谢关键酶DprE1结构的新型抗结核药物筛选、设计和活性评价

项目编号： No.81473254

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李华

作者单位： 华中科技大学

项目金额： 70万元

中文摘要： 据世界卫生组织统计，耐多药结核病造成中国结核病疫情回升，发病率排名世界第二，我国有44.5%的人群感染了结核杆菌，其中活动性肺结核患者超过500万人，每年约有13万人死于该病。寻找新型的、特别是能对抗耐多药结核病的药物是防治结核病的关键。DprE1酶是结核分枝杆菌合成细胞壁所必需的酶，最新的研究表明DprE1酶抑制剂能够有效抑制和杀灭多药抗性的结核杆菌。本项目负责人已经解析了高分辨率的DprE1酶晶体结构，本项目将根据DprE1酶的三维结构，通过最新的计算机虚拟筛选技术对具有2千多万个有机小分子化合物的ZINC数据库进行高通量的虚拟筛选，挑选有希望的化合物进行活性测定，然后解析抑制剂和DprE1酶的复合物晶体结构，根据复合物的晶体结构提出对化合物进行修饰和结构改造的方案，合成一系列化合物，进行药效学实验，从而得到拥有自主知识产权的新型抗结核病先导化合物或候选药物，为最后根治结核病做出贡献。

中文关键词： 结核分枝杆菌；癸异戊烯磷酰基-β-D-核糖2'-差向异构酶；晶体结构；虚拟筛选；抑制剂

英文摘要： According to the statistics of World Health Organization, the MDR-TB epidemic caused the rebound of tuberculosis in China , the incidence rate ranked second in the world. China has 44.5% of the population infected with Mycobacterium tuberculosis , including patients with active tuberculosis more than 5 million people , and about 13 million of them died of the disease each year. Finding novel anti-tuberculosis agents, especially drugs effective on MDR-TB is a key to prevent and cure tuberculosis. DprE1 is an enzyme required for cell wall synthesis in Mycobacterium tuberculosis. The latest research shows that DprE1 inhibitors can effectively inhibit and kill multidrug- resistant Mycobacterium tuberculosis. The leader of this project has sovled the high-resolution crystal structure of DprE1. Based on the three-dimensional structure of the enzyme DprE1 , the current project will use the state-of-art computer technology of virtual screening to perform high throughput screening against the ZINC database,which has more than 20 million small organic molecules, to select promising compounds for further activity assay.Then try to solve the crystal structure of DprE1-inhibitor complex, based on the complex structure, propose further modifications of the compounds.Finnally obtain novel anti-tuberculosis lead compounds or drug candidates with our own interllectual property, and make contributions to eradicate tuberculosis.

英文关键词： M.Tuberculosis;DprE1;Crystal Structure;Virtual Ligand Screening;Inhibitors