丝氨酸及苯基异丝氨酸类SARS病毒3CL蛋白酶抑制剂HQSAR研究及分子设计  

HQSAR study and molecular design of serine and phenylisoserine derivatives as SARS-CoV 3CL protease inhibitors

作　　者：何安朕 张继川 何严萍[2] 王月平[1] HE An-zhen;ZHANG Ji-chuan;HE Yan-ping;WANG Yue-ping(Department of Applied Chemistry,Faculty of Science,Kunming University of Science and Technology,Kunming 650500,Yunnan,China;Key Laboratory of Medicinal Chemistry for Natural Resource,Ministry of Education,School of Chemical Science and Technology/College of Pharmacy,Yunnan University,Kunming 650500,Yunnan,China)

机构地区：[1]昆明理工大学理学院应用化学系,云南昆明650500 [2]云南大学教育部自然资源药物化学重点实验室,化学科学与工程学院·药学院,云南昆明650500

出　　处：《云南大学学报（自然科学版）》2021年第6期1202-1211,共10页Journal of Yunnan University(Natural Sciences Edition)

基　　金：国家自然科学基金(21362017,21967020).

摘　　要：采用分子全息定量构效关系(Holographic Quentitative Structure-Activity Ralationship,HQSAR)方法,研究了40个丝氨酸及苯基异丝氨酸类SARS-CoV 3CL蛋白酶抑制剂的构效关系,探讨了分子碎片大小、碎片区分参数及全息长度对模型质量的影响.利用偏最小二乘法建立了一个以30个化合物为训练集的最优模型,其交叉验证相关系数q^(2)为0.604,非交叉验证相关系数r^(2)为0.904,标准偏差SEE为0.125;使用该模型对由9个化合物组成的测试集进行预测,其预测相关系数r^(2) pred为0.723,表明该模型具有良好的预测能力及拟合能力.利用HQSAR色码图探讨了分子中不同结构片段对活性的贡献,在此基础上根据最优HQSAR模型设计了一组具有良好预测活性的苯基异丝氨酸类3CL蛋白酶抑制剂,为新型SARS-CoV 3CL蛋白酶抑制剂的设计和优化提供了参考,也为研发治疗新型冠状病毒肺炎(COVID-19)的3CL蛋白酶抑制剂提供借鉴.The hologram quantitative structure-activity relationship(HQSAR)was used to study 40 SARS-CoV 3CL protease inhibitors.The molecular fragment distinction parameter,fragment parameter and hologram length that affect the model quality were investigated.Using Partial least squares(PLS)to establish an optimal model with 30 compounds as the training set.In this model cross-validated q^(2) was 0.604,and conventional r^(2) was 0.904,standard deviation SEE was 0.125;The model was used to predict the test set consisting of 9 compounds,and r^(2)pred was 0.723,which indicated that the model had good prediction ability and fitting ability.The color code analysis provided the activity contribution of different groups in the model,and based on this result,a group of phenylisoerine inhibitors with good predictive activity was designed.It provides a reference for the design and optimization of new SARS-CoV 3CL protease inhibitors,and also provides a reference for the development of 3CL protease inhibitors for the treatment of novel coronavirus pneumonia(COVID-19).

关 键 词：冠状病毒 3CL蛋白酶抑制剂 分子全息定量构效关系 色码 分子设计 

分 类 号：O629.71[理学—有机化学] R914[理学—化学]