Predicting hiCE inhibitors based upon pharmacophore models derived from the receptor and its ligands  

作　　者：ZHANG GuoDong GE Hu GU Qiong XU Jun 

机构地区：[1]School of Pharmaceutical Sciences, Sun Yat-sen University

出　　处：《Science China Chemistry》2013年第10期1402-1412,共11页中国科学（化学英文版）

基　　金：funded in part of the National High-tech R&D Program of China(863 Program)(2012AA020307);the introduction of innovative R&D team program of Guangdong Province(2009010058);the National Natural Science Foundation of China(81001372,81173470);the Fundamental Research Funds for the Central Universities(10ykjc01)

摘　　要：Human intestinal carboxyl esterase （hiCE） is a drug target for ameliorating irinotecan-induced diarrhea. By reducing irinotecan- induced diarrhea, hiCE inhibitors can improve the anti-cancer efficacy of irinotecan. To find effective hiCE inhibitors, a new virtual screening protocol that combines pharmacophore models derived from the hiCE structure and its ligands has been pro- posed. The hiCE structure has been constructed through homology techniques using hCESI＇s crystal structure. The hiCE structure was optimized via molecular dynamics simulations with the most known active hiCE inhibitors docked into the structure. An optimized pharmacophore, derived from the receptor, was then generated. A ligand-based pharmacophore was also generated from a larger set of known hiCE inhibitors. The final hiCE inhibitor predictions were based upon the virtual screening hits from both ligand-based and receptor-based pharmacophore models. The hit rates from the ligand-based and receptor-based pharmacophore models are 88% and 86%, respectively. The final hit rate is 94%. The two models are highly consistent with one another （85%）. This proves that both models are reliable.Human intestinal carboxyl esterase(hiCE)is a drug target for ameliorating irinotecan-induced diarrhea.By reducing irinotecaninduced diarrhea,hiCE inhibitors can improve the anti-cancer efficacy of irinotecan.To find effective hiCE inhibitors,a new virtual screening protocol that combines pharmacophore models derived from the hiCE structure and its ligands has been proposed.The hiCE structure has been constructed through homology techniques using hCES1’s crystal structure.The hiCE structure was optimized via molecular dynamics simulations with the most known active hiCE inhibitors docked into the structure.An optimized pharmacophore,derived from the receptor,was then generated.A ligand-based pharmacophore was also generated from a larger set of known hiCE inhibitors.The final hiCE inhibitor predictions were based upon the virtual screening hits from both ligand-based and receptor-based pharmacophore models.The hit rates from the ligand-based and receptor-based pharmacophore models are 88% and 86%,respectively.The final hit rate is 94%.The two models are highly consistent with one another(85%).This proves that both models are reliable.

关 键 词：carboxyl esterase PHARMACOPHORE virtual screening ANTI-CANCER 

分 类 号：R96[医药卫生—药理学]