具有全新机理的DNA旋转酶抑制剂的筛选及抑菌活性

利用具有新机制的抗耐药菌DNA旋转酶抑制剂GSK299423与DNA旋转酶的晶体复合物(PDB code:2XCS)构建基于配体-受体复合物的药效团模型, 诱骗集(Decoy set)验证结果表明该药效团模型具有较强的活性识别能力. 将药效团模型与分子对接相结合用于筛选化合物库, 通过抑菌活性测定, 获得了具有抗多药耐药菌活性的DNA旋转酶抑制剂LTH02.

Virtual Screening and Antibacterial Activity of Novel Inhibitors Targeting the DNA Gyrase with New Mechanism

A new class of DNA gyrase inhibitors such as GSK299423 with new mechanism was reported as potent antibacterial activity against multidrug-resistant bacteria. In this work, crystal structure of GSK299423 in complex of DNA gyrase and DNA(PDB code: 2XCS) was utilized for drug design of novel DNA gyrase inhibitors. A pharmacophore model was constructed via the crystal structure of complex. By decoy set validation, the pharmacophore model was demonstrated to possess favorable ability to recognize novel DNA gyrase inhibitors from library. The pharmacophore model and docking method were applied to virtual screen the Screening Compounds library to obtain hit compounds. The hit compound LTH02 was demonstrated to significantly inhibited multidrug-resistant Escherichia coli by antibacterial activity assay, thus the LTH02 as a novel DNA gyrase inhibitor was finally achieved. The pharmacophore model developed could be applied to design more novel DNA gyrase inhibitors and it also provided theoretical basis for further structural modification and synthesis of the inhibitors.