Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, 382 481, Gujarat, India.
Interdiscip Sci. 2019 Jun;11(2):191-205. doi: 10.1007/s12539-017-0256-1. Epub 2017 Sep 11.
Deazaflavin-dependent nitroreductase (Ddn) is an emerging target in the field of anti-tuberculosis agents. In the present study, 2-nitroimidazooxazine derivatives as Ddn activators were aligned for CoMFA, CoMSIA and HQSAR analysis. The best CoMFA and CoMSIA model were generated with leave-one-out correlation coefficients (q) of 0.585 and 0.571, respectively. Both the CoMFA and CoMSIA models were also validated by a test set of 11 compounds with satisfactory [Formula: see text] value of 0.701 and 0.667, respectively. Results of 3D QSAR and HQSAR study were used for the designing of novel and potent nitroimidazooxazine derivatives as Ddn activators. 21 novel compounds were designed, and docked into the Ddn enzyme. In docking study compound ng11 showed interaction with key amino acid residues such as Tyr65 and Tyr133, and also showed better ADMET compatibility. The ADMET prediction, docking study and the predicted activity of novel designed compounds revealed that compound ng11 showed good potential as Ddn activators for the treatment of tuberculosis.
依赖于去氮黄素的硝基还原酶（Ddn）是抗结核药物领域的一个新兴靶点。在本研究中，我们对 2-硝基咪唑并恶嗪衍生物作为 Ddn 激活剂进行了 CoMFA、CoMSIA 和 HQSAR 分析。最佳的 CoMFA 和 CoMSIA 模型的交叉验证相关系数（q）分别为 0.585 和 0.571。CoMFA 和 CoMSIA 模型也分别通过 11 个化合物的测试集进行了验证，[Formula: see text]值分别为 0.701 和 0.667，结果令人满意。3D-QSAR 和 HQSAR 研究的结果用于设计新型有效的作为 Ddn 激活剂的硝基咪唑并恶嗪衍生物。设计了 21 种新型化合物，并将其对接进入 Ddn 酶。在对接研究中，化合物 ng11 与 Tyr65 和 Tyr133 等关键氨基酸残基相互作用，并且具有更好的 ADMET 兼容性。ADMET 预测、对接研究和新型设计化合物的预测活性表明，化合物 ng11 作为 Ddn 激活剂具有良好的治疗结核病的潜力。
