GVK Biosciences Pvt. Ltd, Plot no: 79, Nacharam, IDA-Mallapur, Hyderabad 500076, Andhra Pradesh, India.
Future Med Chem. 2013 Mar;5(3):249-59. doi: 10.4155/fmc.12.211.
InhA is a promising and attractive target in antimycobacterial drug development. InhA is involved in the reduction of long-chain trans-2-enoyl-ACP in the type II fatty acid biosynthesis pathway of Mycobacterium tuberculosis. Recent studies have demonstrated that InhA is one of the targets for the second line antitubercular drug ethionamide.
In the current study, we have generated quantitative pharmacophore models using known InhA inhibitors and validated using a large test set. The validated pharmacophore model was used as a query to screen an in-house database of 400,000 compounds and retrieved 25,000 hits. These hits were further ranked based on its shape and feature similarity with potent InhA inhibitor using rapid overlay of chemical structures (OpenEye™) and subsequent hits were subjected for docking. Based on the pharmacophore, rapid overlay of chemical structures model and docking interactions, 32 compounds with more than eight chemotypes were selected, purchased and assayed for InhA inhibitory activity. Out of the 32 compounds, 28 demonstrated 10-38% inhibition against InhA at 10 µM.
Further optimization of these analogues is in progress and will update in due course.
InhA 是抗分枝杆菌药物开发中一个有前途且有吸引力的靶标。InhA 参与分枝杆菌型 II 脂肪酸生物合成途径中长链反式-2-烯酰-ACP 的还原。最近的研究表明，InhA 是二线抗结核药物乙硫异烟胺的靶点之一。
在本研究中，我们使用已知的 InhA 抑制剂生成了定量药效团模型，并使用大型测试集进行了验证。验证后的药效团模型被用作查询，筛选了 40 万化合物的内部数据库，得到了 25000 个命中化合物。这些命中化合物根据其与强效 InhA 抑制剂的形状和特征相似性进行了进一步排名，使用快速化学结构叠加（OpenEye™），随后对命中化合物进行了对接。基于药效团、快速化学结构叠加模型和对接相互作用，选择了 32 种具有 8 种以上化学类型的化合物，购买并测试了它们对 InhA 的抑制活性。在这 32 种化合物中，有 28 种在 10µM 时对 InhA 的抑制率为 10-38%。
正在对这些类似物进行进一步优化，并将在适当的时候更新。
