低心血管疾病风险选择性环氧合酶-2抑制剂的虚拟筛选  

Virtual Screening of Selective Cyclooxygenase-2 Inhibitors with Low Cardiovascular Disease Risk

作　　者：萧耿苗 穆云萍 千爱君 李芳红 赵子建 XIAO Geng-miao;MU Yun-ping;QIAN Ai-jun;LI Fang-hong;ZHAO Zi-jianA(School of Biomedical and Pharmaceutical Sciences,Guangdong University of Technology,Guangzhou,Guangdong,510006,Ch)

机构地区：[1]广东工业大学生物医药学院,广东广州510006

出　　处：《现代生物医学进展》2024年第5期807-812,共6页Progress in Modern Biomedicine

基　　金：国家重点研发计划项目(2018YFA0800603);广东省"珠江人才计划"项目(2016ZT06Y432);广东省重点领域研发计划项目(2019B020201015)。

摘　　要：目的:寻找具有血栓素A2受体(Thromboxane A2 receptor,TP)抑制作用的选择性环氧合酶-2(Cyclooxygenase-2,COX-2)抑制剂,以期降低其心血管疾病风险。方法:本研究从公开数据库中获取了512种TP抑制剂,通过分子对接、分子动力学模拟和ADMET预测,筛选出化合物TP84。结果:分子对接结果显示,与先前获批的选择性COX-2抑制剂罗非昔布相比,TP84对COX-2的亲和力更高,对环氧合酶-1(Cyclooxygenase-1,COX-1)的亲和力更低;分子动力学模拟进一步表明,模拟过程中TP84与COX-1的结合不稳定,而TP84能稳定结合COX-2,与COX-2的结合自由能是COX-1的3倍;此外,根据ADMET预测,TP84的药物化学、吸收、分布、代谢、排泄和毒性处于类药物候选物的可接受范围内。结论:TP84是一种潜在的低心血管疾病风险选择性COX-2抑制剂。Objective:To find selective Cyclooxygenase-2(COX-2)inhibitors with thromboxane A2 receptor(TP)inhibition with the aim of reducing their cardiovascular disease risk.Methods:In this study,a total of 512 TP inhibitors were obtained from public databases.Through molecular docking,molecular dynamics simulation,and ADMET prediction,a compound named TP84 was identified.Results:The molecular docking results demonstrate that TP84 exhibits higher affinity for COX-2 and lower affinity for Cyclooxygenase-1(COX-1)compared with rofecoxib,a previously approved selective COX-2 inhibitor.Furthermore,molecular dynamics simulation reveals that TP84 binds unstably to COX-1 during simulations,whereas TP84 can bind COX-2 stably.The binding free energy of TP84 to COX-2 was three times higher than that of COX-1.Furthermore,the medicinal chemistry,absorption,distribution,metabolism,excretion and toxicological properties of TP84 are predicted by ADMET to be within the acceptable range for drug-like candidates.Conclusion:TP84 is a potential selective COX-2 inhibitor drug with low cardiovascular disease risk.

关 键 词：虚拟筛选 选择性COX-2抑制剂 TP抑制剂 低心血管疾病风险 

分 类 号：Q55[生物学—生物化学] Q78[医药卫生—心血管疾病] R54[医药卫生—内科学]