点击次数：

论文类型：期刊论文

发表时间：2009-02-01

发表刊物：BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

收录刊物：SCIE、Scopus

卷号：19

期号：3

页面范围：803-806

ISSN号：0960-894X

关键字：Stereoisomer; CYP2D6; Inhibitor; CoMFA; CoMSIA; Docking; Molecular electrostatic potential

摘要：The distinct inhibitory effects against CYP2D6 enzyme of the stereoisomers quinidine and quinine were investigated in this work by employing various methods, including the comparative molecular field analysis (CoMFA), the comparative molecular similarity indices analysis (CoMSIA), the molecular electrostatic potential (MEP) analysis and the docking method. Several 3D-QSAR models with proper reliability were well established, with a CoMFA model with steric and electrostatic fields exhibiting 0.67, 0.99 and 0.88 of q(2), r(2) and r(2) pred, respectively, a CoMSIA model with steric, electrostatic and H-bond acceptor fields displaying 0.72, 0.97 and 0.84 of q(2), r(2) and r(pred)(2), respectively. These models and related docking results reveal that quinidine binds to CYP2D6 in an inverse orientation as compared with quinine. Moreover, quinidine blocks the entrance of the active pocket of CYP2D6 more closely than quinine does, which explains well why the inhibitory activity of quinidine is of 2 magnitudes larger than quinine. This investigation provides a better understanding of the stereoisometric effects on the bioactivities of the chiral isomers quinidine and quinine interacting with CYP2D6. (C) 2008 Elsevier Ltd. All rights reserved.