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Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-06 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01570 Lijun Song 1 , Romain Merceron 2, 3 , Begoña Gracia 4, 5 , Ainhoa Lucía Quintana 4, 5 , Martijn D. P. Risseeuw 1 , Fabian Hulpia 1 , Paul Cos 6 , José A. Aínsa 4, 5 , Hélène Munier-Lehmann 7 , Savvas N. Savvides 2, 3 , Serge Van Calenbergh 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-06 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01570 Lijun Song 1 , Romain Merceron 2, 3 , Begoña Gracia 4, 5 , Ainhoa Lucía Quintana 4, 5 , Martijn D. P. Risseeuw 1 , Fabian Hulpia 1 , Paul Cos 6 , José A. Aínsa 4, 5 , Hélène Munier-Lehmann 7 , Savvas N. Savvides 2, 3 , Serge Van Calenbergh 1
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In recent years, thymidylate kinase (TMPK), an enzyme indispensable for bacterial DNA biosynthesis, has been pursued for the development of new antibacterial agents including against Mycobacterium tuberculosis, the causative agent for the widespread infectious disease tuberculosis (TB). In response to a growing need for more effective anti-TB drugs, we have built upon our previous efforts toward the exploration of novel and potent Mycobacterium tuberculosis TMPK (MtTMPK) inhibitors, and reported here the design of a novel series of non-nucleoside inhibitors of MtTMPK. The inhibitors display hitherto unexplored interactions in the active site of MtTMPK, offering new insights into structure–activity relationships. To investigate the discrepancy between enzyme inhibitory activity and the whole-cell activity, experiments with efflux pump inhibitors and efflux pump knockout mutants were performed. The minimum inhibitory concentrations of particular inhibitors increased significantly when determined for the efflux pump mmr knockout mutant, which partly explains the observed dissonance.
中文翻译：
结构引导的铅向非手性结核分枝杆菌胸苷酸激酶抑制剂的产生。
近年来，一直致力于开发细菌DNA生物合成必不可少的酶胸苷酸激酶（TMPK），以开发新的抗菌剂，包括抗结核分枝杆菌（结核分枝杆菌）。为了应对对更有效的抗结核药物的日益增长的需求，我们在先前探索新型和有效结核分枝杆菌TMPK（Mt TMPK）抑制剂的努力基础上，在此报告了一系列新型非核苷的设计的抑制剂山TMPK。抑制剂在Mt的活性位点显示出迄今未探索的相互作用TMPK，提供有关结构与活动关系的新见解。为了研究酶抑制活性和全细胞活性之间的差异，进行了外排泵抑制剂和外排泵敲除突变体的实验。当确定外排泵mmr敲除突变体时，特定抑制剂的最小抑制浓度显着增加，这部分解释了观察到的不和谐。
更新日期：2018-03-06
中文翻译：
结构引导的铅向非手性结核分枝杆菌胸苷酸激酶抑制剂的产生。
近年来，一直致力于开发细菌DNA生物合成必不可少的酶胸苷酸激酶（TMPK），以开发新的抗菌剂，包括抗结核分枝杆菌（结核分枝杆菌）。为了应对对更有效的抗结核药物的日益增长的需求，我们在先前探索新型和有效结核分枝杆菌TMPK（Mt TMPK）抑制剂的努力基础上，在此报告了一系列新型非核苷的设计的抑制剂山TMPK。抑制剂在Mt的活性位点显示出迄今未探索的相互作用TMPK，提供有关结构与活动关系的新见解。为了研究酶抑制活性和全细胞活性之间的差异，进行了外排泵抑制剂和外排泵敲除突变体的实验。当确定外排泵mmr敲除突变体时，特定抑制剂的最小抑制浓度显着增加，这部分解释了观察到的不和谐。
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