新型细菌拓扑异构酶抑制剂作用靶点——DNA促旋酶的结构研究
Structural Aspects of DNA Gyrase Targeted by Novel Bacterial Topoisomerase Inhibitors.
作者信息
Kokot Maja, Hrast Rambaher Martina, Feng Lipeng, Mitchenall Lesley A, Lawson David M, Maxwell Anthony, Parish Tanya, Minovski Nikola, Anderluh Marko
机构信息
Theory Department, Laboratory for Cheminformatics, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
出版信息
ACS Med Chem Lett. 2024 Nov 22;15(12):2164-2170. doi: 10.1021/acsmedchemlett.4c00447. eCollection 2024 Dec 12.
In this Letter, we present a small series of novel bacterial topoisomerase inhibitors (NTBIs) that exhibit both potent inhibition of DNA gyrase and potent antimycobacterial activity. The disclosed crystal structure of DNA gyrase in complex with DNA and compound from this NBTI series reveals the binding mode of an NBTI in the GyrA binding pocket and confirms the presence and importance of halogen bonding for the excellent on-target potency. In addition, we have shown that compound is a promising DNA gyrase inhibitor, with an IC for gyrase of 0.096 μM, and it has potent activity against , with an IC of 0.165 μM.
在本信函中，我们展示了一小系列新型细菌拓扑异构酶抑制剂（NTBIs），它们对DNA促旋酶具有强效抑制作用且具备强效抗分枝杆菌活性。所披露的该NTBI系列中与DNA及化合物形成复合物的DNA促旋酶晶体结构揭示了一种NTBI在GyrA结合口袋中的结合模式，并证实了卤键对于出色的靶向活性的存在及重要性。此外，我们已表明该化合物是一种有前景的DNA促旋酶抑制剂，其对促旋酶的IC50为0.096 μM，并且它对[具体细菌名称未给出]具有强效活性，IC50为0.165 μM。
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