title: Insight into the effects of chiral isomers quinidine and quinine on CYP2D6 inhibition.
abstract: 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(pred)(2), 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.
authors.affiliation: Lab of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.
authors.forename: Chunzhi
authors.initials: C
authors.lastname: Ai
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Wang
authors.forename: Yadong
authors.initials: Y
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008968:Molecular Conformation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D011802:Quinidine / Q000737:chemistry*; D011803:Quinine / Q000737:chemistry*; D055672:Static Electricity; D013237:Stereoisomerism
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D011803:Quinine; D011802:Quinidine