抗耐药性结核病新药的先导化合物筛选  

Screening of lead compounds for new drugs against drug-resistant tuberculosis

作　　者：刘思含 王潇[1] 关艳[1] 刘忆霜[1] 肖春玲[1] 蒙建州[1] LIU Si-han;WANG Xiao;GUAN Yan;LIU Yi-shuang;XIAO Chun-ling;MENG Jian-zhou(National Laboratory for Screening New Microbial Drugs,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院北京协和医学院医药生物技术研究所国家新药(微生物)筛选实验室,北京100050

出　　处：《中国医药生物技术》2022年第2期104-110,共7页Chinese Medicinal Biotechnology

基　　金：国家自然科学基金(81803412、81903678);中国医学科学院医学与健康科技创新工程(2016-I2M-1-013)。

摘　　要：目的 采用结核分枝杆菌(Mtb)H37Rv对从上海陶塑生物科技有限公司购买的生物活性化合物库L4000进行抑制剂筛选,以获得具有成药前景的抗结核先导化合物。方法 采用已经建立的MtbH37Rv细胞水平的抑制剂高通量筛选模型对化合物库L4000的7285个样品进行筛选,并测定初筛阳性化合物对H37Rv以及临床多药耐药结核分枝杆菌的最低抑菌浓度,获得具有抗结核活性的阳性样品;进一步采用网络分析工具Swiss-ADME、Molsoft对阳性样品进行成药性分析。结果 从7285个化合物中共获得411个具有抗结核活性的化合物,初筛阳性率为5.64%;进一步测定它们对Mtb H37Rv、临床多药耐药Mtb 28和1731的最低抑菌浓度,获得24个具有明显抑制活性的化合物,总体阳性率为0.33%;采用Swiss-ADME对这24个抗结核化合物进行药化性质分析,并利用Molsoft对具有成药前景的化合物进行验证。最终获得具有成药前景的化合物LTBI371,该化合物对各种Mtb都表现出极强的抑制活性。结论 基于生物活性的化合物库开展抗结核药物筛选将更有可能获得对临床耐药Mtb具有抑制活性的阳性样品。Objective To obtain prospective anti-tuberculosis lead compounds from the bio-active compound library L4000 by using Mycobacterium tuberculosis(Mtb) H37Rv.Methods A collection of 7285 compounds of L4000 library was screened with the cellular inhibitor high-throughput screening model based on Mtb H37Rv, and the minimum inhibitory concentrations(MICs) of the first-screening positive compounds against H37Rv and clinical multidrug-resistant(MDR) Mtb were determined so that anti-tuberculosis compounds were obtained.Subsequently, network analysis software Swiss-ADME and Molsoft were used to analyze the medicinal properties of these bacteriostatic agents.Results A total of 411 compounds with anti-tuberculosis activity were obtained from 7285 compounds with a first-screening positive rate of 5.64%. Their MICs against Mtb H37Rv, clinical multidrug-resistance Mtb strains 28 and 1731 were further determined. Based on this, we obtained 24 compounds with obvious inhibitory activities with an overall positive rate of 0.33%.Swiss-ADME and Molsoft were used to analyze the pharmacochemical properties and drug-likeness of these 24 anti-tuberculosis compounds, respectively. Lastly we obtained a promising compound LTBI371 with admirable inhibitory activities against all Mtb strains.Conclusion Screening through the bio-active compound libraries makes it more likely to obtain promising samples with inhibitory activities against clinical resistant Mtb.

关 键 词：结核分枝杆菌 多药耐药 表型筛选 抗结核化合物 

分 类 号：R978.3[医药卫生—药品]