3-氨磺酰苯甲酸类AKR1C3抑制剂的3D-QSAR和分子对接研究

醛酮还原酶1C3(AKR1C3)作为治疗前列腺癌的新靶点已成为研究热点,3-氨磺酰苯甲酸衍生物对其具有高效的选择性和抑制活性。本文采用比较分子场分析(COMFA)和比较分子相似性指数分析(COMSIA)方法,将经分子对接后的34个优势构象组成训练集和11个优势构象组成测试集,构建三维定量构效关系(3D-QSAR)模型。COMFA模型的交叉验证系数(q2),非交叉验证系数(R2),标准偏差(SEE)和F值分别为0.761,0.973,0.122,185.963;自举法回归系数为R2bs=0.98。最佳组合COMSIA模型的q2,R2,SEE,F和R2bs分别为0.734,0.984,0.097,147.850,0.994。COMFA和COMSIA模型的系统外部测试R2pred分别为0.864和0.756,r2m分别为0.8127和0.5377。这些结果表明,所建立的QSAR模型具有较高的可靠性和较强预测能力。经三维等势图分析可知,在2、5或6位适当增加取代基体积,或在5位引入氢键受体,或在7位引入负电性取代基则能提高化合物的生物活性。该模型为进一步设计具有更优选择性和活性的化合物提供了理论依据。

3D-QSAR and Molecular Docking Study of 3-Sulfamoylbenzoic Acid Derivatives as AKR1C3 Inhibitors

The human aldo-keto reductase family 1 member C3 (AKR1C3) has became a significant emerging target of therapeutic interest in prostate cancers. In the present work, 3D-QSAR model was established by a training set of 34 compounds and validated by the evaluation of a test set of 11 compounds, using the comparative molecular field analysis (COMFA) and comparative molecular similarity indices analysis (COMSIA) methods. The q2, R2, SEE, F and the R2bs were 0.761, 0.973, 0.122, 185.963 and 0.98 respectively in COMFA model, and were 0.734, 0.984, 0.097, 147.850, and 0.994 respectively in optimum COMSIA model. The established 3D-QSAR model shows strong stability and good predictive ability. The systemic external validation parameters for COMFA and COMSIA models were R2pred (0.864 and 0.756) and r2m (0.8137 and 0.5377), which validate the quality and predictive ability of 3D-QSAR model. Based on the 3D contour maps, if the volume of the substituent are increased appropriately at the 2, 5 or 6 positions of the template molecule, or hydrogen bond acceptor substituent was added to the 5 position of the template molecule, or the electronegative substituent was added to the 7 position of the template molecule, the biological activity of compounds will be improved. The generated models can provide useful information for designing new compounds with higher selectivity and stronger activity.