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

作　　者：康家雄 朱江[2] 李爱秀 肖泽云 李凯[1,5] KANG Jia-xiong;ZHU Jiang;LI Ai-xiu;XIAO Ze-yun;LI Kai(Drug Design Laboratory of the Basic Courses Department,Logistics University of PAP,Tianjin 300309,China;Department of Health Service,Logistics University of PAP,Tianjin 300309,China;Armed Police Forces Hospital of Sichuan,Leshan 614000,China;Tianjin Key Laboratory for Biomarkers of Occupational and Environmental Hazard,Tianjin 300309,China;Pharmacy Department,Shanxi General Hospital of PAP,Taiyuan 030006,China)

机构地区：[1]中国人民武装警察部队武警后勤学院基础部药物设计实验室,天津300309 [2]中国人民武装警察部队武警后勤学院卫勤系,天津300309 [3]武警四川省总队医院,乐山614000 [4]天津市职业与环境危害防制重点实验室,天津300309 [5]武警山西总队医院药剂科,太原030006

出　　处：《中国新药杂志》2019年第23期2885-2892,共8页Chinese Journal of New Drugs

基　　金：国家自然科学基金项目(81241114,30472166);天津市科技攻关计划重点科技攻关专项基金资助项目(06YFGZSH07000);武警后勤学院研究生创新课题(WHYC201605);武警后勤学院科研创新团队。

摘　　要：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.

关 键 词：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 类似物 遗传函数逼近法 二维定量构效关系 

分 类 号：R914.5[医药卫生—药物化学]