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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。
Aldosterone reductase 1C3 (AKR1C3) has become a hot research topic for the treatment of prostate cancer, and 3-sulfamoyl benzoic acid derivatives have high selectivity and inhibitory activity. In this paper, we use the comparative molecular field analysis (COMFA) and comparative molecular similarity index analysis (COMSIA) method to construct the test set of 34 dominant conformations by molecular docking and 11 dominant conformations to construct the three-dimensional quantitative structure-activity relationship 3D-QSAR) model. The cross-validation coefficient (q2), non-cross-validation coefficient (R2), standard deviation (SEE) and F value of the COMFA model are 0.761, 0.973, 0.122 and 185.963, respectively. The regression coefficient of the bootstrap method is R2bs = 0.98. The q2, R2, SEE, F and R2bs of the best combination COMSIA model were 0.734, 0.984, 0.097, 147.850 and 0.994, respectively. The system external tests R2pred of COMFA and COMSIA models were 0.864 and 0.756, respectively, and r2m was 0.8127 and 0.5377 respectively. These results show that the established QSAR model has high reliability and strong predictive ability. The three-dimensional isoelectric point analysis showed that increasing the volume of the substituent at the 2, 5 or 6 position or introducing hydrogen bond acceptor at the 5 position or introducing the negatively charged substituent at the 7 position increased the biological activity of the compound. The model provides a theoretical basis for the further design of compounds with better selectivity and activity.