Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen.
Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen.
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DOI：
10.1038/srep38986
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发表时间：
2016-12-16
影响因子：
4.6
通讯作者：
Besra GS
中科院分区：
文献类型：
--
作者：
Cox JA;Mugumbate G;Del Peral LV;Jankute M;Abrahams KA;Jervis P;Jackenkroll S;Perez A;Alemparte C;Esquivias J;Lelièvre J;Ramon F;Barros D;Ballell L;Besra GS
高通量表型筛选已重新成为抗生素发现中的筛选工具。这些技术的出现迅速加速了“命中”化合物的鉴定。药物化学优化程序的一个先决条件，需要改善药物样性质的“命中”分子是确定其作用模式。在此，我们将表型筛选与有偏见的靶特异性筛选相结合。肌苷单磷酸脱氢酶（IMPDH）蛋白GuaB2已被鉴定为结核分枝杆菌中的可药用靶标，然而先前鉴定的化合物缺乏进一步开发成铅样分子所需的期望特征。本研究从使用过表达GuaB2的牛分枝杆菌BCG的高通量基于抗性的表型筛选中鉴定了7个新的化学系列。在单次高通量筛选中鉴定命中化合物，通过剂量反应验证并进行进一步的生化分析。还使用分子对接实验对化合物进行了评估，为使用药物化学对其进行进一步优化提供了平台。这项工作证明了GuaB2作为抗结核药物靶标的多功能性和潜力。
High-throughput phenotypic screens have re-emerged as screening tools in antibiotic discovery. The advent of such technologies has rapidly accelerated the identification of ‘hit’ compounds. A pre-requisite to medicinal chemistry optimisation programmes required to improve the drug-like properties of a ‘hit’ molecule is identification of its mode of action. Herein, we have combined phenotypic screening with a biased target-specific screen. The inosine monophosphate dehydrogenase (IMPDH) protein GuaB2 has been identified as a drugable target in Mycobacterium tuberculosis, however previously identified compounds lack the desired characteristics necessary for further development into lead-like molecules. This study has identified 7 new chemical series from a high-throughput resistance-based phenotypic screen using Mycobacterium bovis BCG over-expressing GuaB2. Hit compounds were identified in a single shot high-throughput screen, validated by dose response and subjected to further biochemical analysis. The compounds were also assessed using molecular docking experiments, providing a platform for their further optimisation using medicinal chemistry. This work demonstrates the versatility and potential of GuaB2 as an anti-tubercular drug target.
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影响因子：
14.9
作者：
Gutmanas A;Alhroub Y;Battle GM;Berrisford JM;Bochet E;Conroy MJ;Dana JM;Fernandez Montecelo MA;van Ginkel G;Gore SP;Haslam P;Hatherley R;Hendrickx PM;Hirshberg M;Lagerstedt I;Mir S;Mukhopadhyay A;Oldfield TJ;Patwardhan A;Rinaldi L;Sahni G;Sanz-García E;Sen S;Slowley RA;Velankar S;Wainwright ME;Kleywegt GJ
通讯作者：
Kleywegt GJ
影响因子：
9.6
作者：
Velayati, Ali Akbar;Masjedi, Mohammad Reza;Hoffner, Sven Eric
通讯作者：
Hoffner, Sven Eric
影响因子：
2.8
作者：
Usha, Veeraraghavan;Gurcha, Sudagar S.;Besra, Gurdyal S.
通讯作者：
Besra, Gurdyal S.
影响因子：
3.1
作者：
Matteelli A;Carvalho AC;Dooley KE;Kritski A
通讯作者：
Kritski A
影响因子：
3.5
作者：
Neves, Marco A. C.;Totrov, Maxim;Abagyan, Ruben
通讯作者：
Abagyan, Ruben