结核分枝杆菌
肺结核
药物发现
化学
表型筛选
拉伤
活动站点
计算生物学
酶
表型
药物靶点
组合化学
立体化学
生物化学
生物
医学
基因
病理
解剖
作者
Martyn Frederickson,Irwin Selvam,Dimitrios Evangelopoulos,Kirsty J. McLean,Mona M. Katariya,Richard B. Tunnicliffe,Bethany Campbell,Madeline E. Kavanagh,Sitthivut Charoensutthivarakul,Richard T. Blankley,Colin Levy,Luiz Pedro S. de Carvalho,D. Leys,Andrew W. Munro,Anthony G. Coyne,Chris Abell
标识
DOI:10.1016/j.ejmech.2022.114105
摘要
There is a pressing need for new drugs against tuberculosis (TB) to combat the growing resistance to current antituberculars. Herein a novel strategy is described for hit generation against promising TB targets involving X-ray crystallographic screening in combination with phenotypic screening. This combined approach (XP Screen) affords both a validation of target engagement as well as determination of in cellulo activity. The utility of this method is illustrated by way of an XP Screen against CYP121A1, a cytochrome P450 enzyme from Mycobacterium tuberculosis (Mtb) championed as a validated drug discovery target. A focused screening set was synthesized and tested by such means, with several members of the set showing promising activity against Mtb strain H37Rv. One compound was observed as an X-ray hit against CYP121A1 and showed improved activity against Mtb strain H37Rv under multiple assay conditions (pan-assay activity). Data obtained during X-ray crystallographic screening were utilized in a structure-based campaign to design a limited number of analogues (less than twenty), many of which also showed pan-assay activity against Mtb strain H37Rv. These included the benzo[b][1,4]oxazine derivative (MIC90 6.25 μM), a novel hit compound suitable as a starting point for a more involved hit to lead candidate medicinal chemistry campaign.
科研通智能强力驱动
Strongly Powered by AbleSci AI