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3D-QSAR、分子对接研究及硫霉素类似物作为 mtFabH 抑制剂的结合模式预测。

3D-QSAR, molecular docking studies, and binding mode prediction of thiolactomycin analogs as mtFabH inhibitors.

机构信息

Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.

出版信息

J Enzyme Inhib Med Chem. 2010 Apr;25(2):240-9. doi: 10.3109/14756360903049059.

DOI:10.3109/14756360903049059

PMID:19968566

Abstract

Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III (mtFabH) has been identified as a novel target for treating tuberculosis. The aim of this study was to understand the binding affinities of thiolactomycin (TLM) analogs for mtFabH based on 3D quantitative structure-activity relationship (3D-QSAR) analysis and molecular docking studies. The 3D-QSAR models produced statistically significant results (comparative molecular field analysis (CoMFA) r2 cv = 0.701, r(2) = 0.988; comparative molecular similarity indices analysis (CoMSIA) r2 cv = 0.625, r(2) = 0.969) with 40 TLM analogs. In particular, compounds possessing hydrogen bond acceptors attached to the end of side chains at the C5 position of TLM analogs may enhance their activity. The results of 3D-QSAR models were further compared with structure-based analysis using docking studies with the crystal structure of mtFabH. A plausible binding mode between TLM analogs and mtFabH is proposed.

摘要

结核分枝杆菌β-酮酰基酰基辅酶 A 合酶 III（mtFabH）已被确定为治疗结核病的新靶标。本研究旨在基于三维定量构效关系（3D-QSAR）分析和分子对接研究了解硫内酯（TLM）类似物与 mtFabH 的结合亲和力。所产生的 3D-QSAR 模型具有统计学意义（比较分子场分析（CoMFA）r2 cv = 0.701，r2 = 0.988；比较分子相似性指数分析（CoMSIA）r2 cv = 0.625，r2 = 0.969），涉及 40 个 TLM 类似物。特别是，具有氢键受体的化合物附着在 TLM 类似物的 C5 位置的侧链末端，可能会增强其活性。3D-QSAR 模型的结果进一步通过与 mtFabH 的晶体结构进行对接研究的基于结构的分析进行了比较。提出了 TLM 类似物与 mtFabH 之间的合理结合模式。