PD-1/PD-L1抑制剂的三维定量构效关系和分子对接研究  

Three-dimensional quantitative structure-activity relationship and molecular docking of PD-1/PD-L1 inhibitors

作　　者：张璐 赵学敏 张清昱 戴晨 余秀燕 黄奎龙 沈燕 林治华 ZHANG Lu;ZHAO Xuemin;ZHANG Qingyu;DAI Chen;YU Xiuyan;HUANG Kuilong;SHEN Yan;LIN Zhihua(College of Pharmacy and Biological Engineering,Chongqing University of Technology,Chongqing 400054,China)

机构地区：[1]重庆理工大学药学与生物工程学院,401320

出　　处：《免疫学杂志》2023年第1期60-69,共10页Immunological Journal

基　　金：重庆理工大学科研启动基金(2022ZDZ008);重庆理工大学研究生创新项目(gzlcx20223346,gzlcx20223353)。

摘　　要：目的探讨程序性死亡受体-1(PD-1)、程序性死亡受体配体-1(PD-L1)抑制剂的三维定量构效关系和分子对接研究。方法针对现有的小分子化合物进行合理研究,取45个新型o-(联苯-3-基甲/氧基)硝基苯抑制剂进行三维定量构效关系研究,包括使用分子力场分析法(comparative molecular field analysis,CoMFA)和比较分子相似性指数法(comparative molecular similarity indices analysis,CoMSIA),并且对分子对接,观察小分子与5J89蛋白的结合效果。结果Co MFA模型(q^(2)=0.644,r^(2)=0.950)和CoMSIA模型(q^(2)=0.622,r^(2)=0.998)具有一定预测能力。TYR:56、GLN:66氨基酸是影响这些抑制剂活性的主要氨基酸。结论该研究是计算机辅助药物方法在抗肿瘤方面的应用,可为开发PD-1/PD-L1抑制剂作为抗癌药物提供参考。This study was performed to investigate the three-dimensional quantitative structure-activity relationship and molecular docking of programmed death receptor-1(PD-1)and programmed death receptor ligand-1(PD-L1)inhibitors.Total of 45 novel O-(biphenyl-3-ylmethyl/oxy)nitrobenzene inhibitors were selected for three-dimensional quantitative structure-activity relationship studies by using molecular field analysis(CoMFA)and comparative molecular similarity indices analysis(CoMSIA),and molecules docking was carried out to observe the binding effect of small molecules to 5J89 protein.Data showed that the CoMFA model(q^(2)=0.644,r^(2)=0.950)and the CoMSIA model(q^(2)=0.622,r^(2)=0.998)have certain predictive capabilities.TYR:56 and GLN:66 amino acids are the main amino acids that affect the activity of these inhibitors.The application of computer-assisted method in antitumor drug design demonstrated in this paper is helpful for the development of PD-1/PD-L1 inhibitors as anticancer drugs.

关 键 词：程序性死亡受体-1 程序性死亡受体配体-1 抑制剂 三维定量构效关系 分子对接 

分 类 号：R914.2[医药卫生—药物化学]