Mycobacterium tuberculosis DNA gyrase subunit B (GyrB) has been identified as a promising target for rational drug design against fluoroquinolone drug-resistant tuberculosis. In this study, we attempted to identify the key structural feature for highly potent GyrB inhibitors through 2D-QSAR using HQSAR, 3D-QSAR using CoMSIA and molecular dynamics (MD) simulations approaches on a series of thiazole urea core derivatives. The best HQSAR and CoMSIA models based on IC₅₀ and MIC displayed the structural basis required for good activity against both GyrB enzyme and mycobacterial cell. MD simulations and binding free energy analysis using MM-GBSA and waterswap calculations revealed that the urea core of inhibitors has the strongest interaction with Asp79 via hydrogen bond interactions. In addition, cation-pi interaction and hydrophobic interactions of the R₂ substituent with Arg82 and Arg141 help to enhance the binding affinity in the GyrB ATPase binding site. Thus, the present study provides crucial structural features and a structural concept for rational design of novel DNA gyrase inhibitors with improved biological activities against both enzyme and mycobacterial cell, and with good pharmacokinetic properties and drug safety profiles.

结核分枝杆菌DNA 促旋酶亚基 B (GyrB) 已被确定为针对氟喹诺酮耐药结核病的合理药物设计的有希望的目标。在这项研究中，我们尝试通过使用 HQSAR 的 2D-QSAR、使用 CoMSIA 的 3D-QSAR 和一系列噻唑尿素核心衍生物的分子动力学 (MD) 模拟方法来确定高效 GyrB 抑制剂的关键结构特征。_{基于 IC 50}的最佳 HQSAR 和 CoMSIA 模型和 MIC 展示了对 GyrB 酶和分枝杆菌细胞具有良好活性所需的结构基础。使用 MM-GBSA 和水交换计算的 MD 模拟和结合自由能分析表明，抑制剂的尿素核心通过氢键相互作用与 Asp79 具有最强的相互作用。_{此外，R 2}取代基与 Arg82 和 Arg141的阳离子-π 相互作用和疏水相互作用有助于增强 GyrB ATPase 结合位点的结合亲和力。因此，本研究为新型 DNA 促旋酶抑制剂的合理设计提供了重要的结构特征和结构概念，这些抑制剂具有针对酶和分枝杆菌细胞的改进的生物活性，并且具有良好的药代动力学特性和药物安全性。