MKC-442及其类似物的二维定量构效关系

2-dimensional quantitative structure-activity relationship of MKC-442 and its analogues

目的:探究影响人类免疫缺陷病毒Ⅰ型(human immunodeficiency virus type 1,HIV-1)非核苷类逆转录酶抑制剂6-苄基-1-乙氧甲基-5-异丙基尿嘧啶[6-benzyl-1-(ethoxymethyl)-5-isopropyluracil,MKC-442]及其类似物抗病毒活性的主要分子微观结构因素。方法:针对45个MKC-442及其类似物,利用遗传函数逼近法(genetic function approximation,GFA)构建10个抗HIV-1活性与优选的分子结构描述符之间的二维定量构效关系(2-dimensional quantitative structure-activity relationship,2D-QSAR)模型,从中挑选出最优模型并对其进行验证,据此阐明影响MKC-442及其类似物抗HIV-1活性的主要微观结构因素。结果:最优2D-QSAR模型的非交叉验证相关系数r2为0.7845,交叉验证相关系数q2为0.6958,预测验证相关系数r2pred为0.8415,表明其具有较高的预测能力和稳定性。结论:研究表明,MKC-442及其类似物抗HIV-1活性主要与描述符JursFNSA2,ShadowYZ,DipoleX,Kappa3AM和CHIV3P相关,为MKC-442及其类似物的进一步结构修饰打下了一定的理论基础。

Objective:To explore the primary molecular microstructural factors affecting antiviral activity of6-benzyl-1-(ethoxymethyl)-5-isopropyluracil(MKC-442)and its analogues as human immunodeficiency virus type1(HIV-1)non-nucleoside reverse transcriptase inhibitors.Methods:Ten 2-dimensional quantitative structureactivity relationship(2D-QSAR)models were constructed for 45 MKC-442 and its analogues between anti-HIV-1activity and the preferred molecular structure descriptors via genetic function approximation(GFA),from which the optimal model was selected and validated.The primary factors affecting the anti-HIV-1 activity of MKC-442 and its analogues were elucidated.Results:As the best 2D-QSAR model,the non-cross-validated value(r2)was 0.7845,the cross-validated value(q2)was 0.6958,and the prediction-validated value(r2pred)was 0.8415,indicating that it possessed high predictability and robustness.Conclusion:The results clearly indicated that the anti-HIV-1 activity of MKC-442 and its analogues were mainly governed by JursFNSA2,ShadowYZ,DipoleX,Kappa3AM and CHIV3P,laying a certain theoretical foundation for further structural modifications of MKC-442 and its analogues.