title: Mechanistic studies for tri-targeted inhibition of enzymes involved in cholesterol biosynthesis by green tea polyphenols.
abstract: In the present study, we found that three enzymes, MVK, MDD and FPPS, in the mevalonate pathway (MVP) of cholesterol biosynthesis, can be simultaneously inhibited by two green tea polyphenols ((-)-epicatechin-3-gallate, ECG; (-)-epigallocatechin-3-gallate, EGCG). Molecular dynamics simulations and pharmacophore studies were carried out to elucidate the tri-targeted inhibition mechanisms. Our results indicate that similar triangular binding pockets exist in all three enzymes, which is essential for their binding with polyphenols. Two distinct binding poses for ECG and EGCG were observed in our MD simulations. These results shed light on the potential for further selective and multi-targeted inhibitor design for the treatment of hyperlipidemia.
authors.affiliation: School of Pharmaceutical Sciences & Institute of Human Virology, Sun Yat-Sen University, 132 East Circle Road at University City, Guangzhou, 510006, China. junxu@biochemomes.com liding@mail.sysu.edu.cn.
authors.forename: Hu
authors.initials: H
authors.lastname: Ge
authors.forename: Jinggong
authors.initials: J
authors.lastname: Liu
authors.forename: Wenxia
authors.initials: W
authors.lastname: Zhao
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Qingqing
authors.initials: Q
authors.lastname: He
authors.forename: Ruibo
authors.initials: R
authors.lastname: Wu
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
mesh_terms: D000818:Animals; D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors / Q000737:chemistry; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002784:Cholesterol / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000737:chemistry; D051381:Rats; D013662:Tea
chemical_list: D004791:Enzyme Inhibitors; D013662:Tea; D002392:Catechin; C062669:epicatechin gallate; D002784:Cholesterol; C045651:epigallocatechin gallate; D051228:Geranyltranstransferase; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D002262:Carboxy-Lyases; C022503:pyrophosphomevalonate decarboxylase