A new method for screening of selective COX-2 inhibitors over COX-1 by pharmacophore models
Its necessary to search new scaffold of selective COX-2 inhibitors to avoid cardiovascular toxicity in use and to further study anticancer activity.We aim at budding pharmacophore models of COX-2 and COX-1,and using the two models for virtual screening,compounds with low estimated IC50 values of COX-2 but high estimated IC50 values of COX-1 will be hits.In this article,pharmacophore model of COX-2 inhibitors was established with correlation coefficient of 0.94,root mean square deviation (RMSD) of 1.20 and cost difference of 74,while pharmacophore model of COX-1 inhibitors was generated with correlation coefficient of 0.96,RMSD of 1.23 and cost difference of 140.Then the two hypotheses were validated by Fischers randomization,test set and ROC curve analysis.Selective screening ability validation shows the two pharmacophore models have certain selective ability for COX-2 inhibitors over COX-1.Then 87337 drug-like compounds from ZINC database were used for virtual screening by these two pharmacophores and 7 selective COX-2 inhibitors over COX-1 were found.The 7 hits can dock into COX-2 protein well but only 1 is able to dock into COX-1 protein with poor docking scores.In conclusion,our new method proves useful and reliable in screening selective COX-2 inhibitors over COX-1.
COX-2 inhibitors COX-1 inhibitors selective pharmacophore models Discovery Studio 2.5 virtual screening docking
Zhi Cao Yueqing Li Junfeng Gu Weijie Zhao Xicheng Wang
School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024, P.R State Key Laboratory of Structure Analyses for Industrial Equipment, Dalian University of Technology
国际会议
南京
英文
13-13
2012-05-13（万方平台首次上网日期，不代表论文的发表时间）