基于分子模拟新型骨架DprE1酶抑制剂的构建、设计及抗耐药结核分枝杆菌构效关系研究

项目名称： 基于分子模拟新型骨架DprE1酶抑制剂的构建、设计及抗耐药结核分枝杆菌构效关系研究

项目编号： No.21503272

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 数理科学和化学

项目作者： 刘吉元

作者单位： 西北农林科技大学

项目金额： 21万元

中文摘要： 结核病是患病率及死亡率最高的疾病之一。由于多重耐药和广谱耐药结核病的出现，现有抗结核病药物已不能满足治愈需求，研发抗结核新药迫在眉睫。结核分枝杆菌具有复杂的细胞壁，对大多数常用抗生素具有抗性，阻碍细胞壁的形成是目前开发抗结核药物的主要思路。DprE1 酶能够阻断结核分枝杆菌细胞壁必要组成部分阿拉伯聚糖的合成，杀死细菌;DprE1存在于病原体，人类宿主细胞中没有相关同源蛋白，成为不同于现有抗结核病药物靶点全新的抗结核药物靶点。.2014年12月DprE1完整晶体结构被解析，为深入研究DprE1酶与其抑制剂之间相互作用机制以及设计新型骨架抑制剂提供了可能。本项目将采用分子动力学、药效团、分子对接及结合自由能计算等分子模拟技术，构建出用于发现新型骨架DprE1抑制剂的高通量虚拟筛选方法和流程，通过构效关系研究，设计和开发出对耐药性结核杆菌的高效药物，为全新抗结核药物的开发提供新的思路和方法。

中文关键词： 药效团模型；高通量药物虚拟筛选；分子动力学模拟；药物从头设计；分子对接

英文摘要： Tuberculosis is one of the diseases with the highest morbidity and mortality, developing its novel antagonists is urgently required especially when taking the low activity of current drugs caused by multi-drug and broad-spectrum resistant strains into consideration. Mycobacterium tuberculosis is resistant to the dominant antibiotics partly due to its sophisticated cytoderm, so impeding the formation of cytoderm currently acts as the main idea to develop anti-tuberculosis drugs. DprE1 is an enzyme to interdict the synthesis of Araexclude, an essential component of the cytoderm of M. tuberculosis, hence causing its death. Because of the pathogen-specific characteristic of DprE1, it has become a totally new drug target to control tuberculosis..Uncovering the interaction mechanism between DprE1 and its inhibitors and designing new framework inhibitors of DprE1 become possible with the resolution of DprE1 crystal structure. In this project, to construct high throughput drug screening of the DprE1 inhibitors with new framework and to study the structure-activity relationship between the new inhibitors and M. Tuberculois, molecular simulation techniques including molecular dynamics simulation, pharmacophore model, molecular docking and binding free energy calculation etc. are approached to be taken. Designing novel framework inhibitors based on the study of their strucrue-activity realtionship with M. tuberculosis would be a new way to develop totally novel drugs of high efficiency to drug-resistant strains.

英文关键词： pharmacophore model;high-throughput drug screening;molecular dynamics simulations;drug de novo design;molecular docking