A new method for screening of selective COX-2 inhibitors over COX-1 by pharmacophore models

摘要

It's 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 Fischer's 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.