Insight into the effects of chiral isomers quinidine and quinine on CYP2D6 inhibition.

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.

[1]  F. Guengerich,et al.  Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies. , 1993, Journal of medicinal chemistry.

[2]  G. S. Walker,et al.  Inhibition of cytochrome P450 2D6: structure-activity studies using a series of quinidine and quinine analogues. , 2003, Chemical research in toxicology.

[3]  Ajay N. Jain.  Scoring noncovalent protein-ligand interactions: A continuous differentiable function tuned to compute binding affinities , 1996, J. Comput. Aided Mol. Des..

[4]  S A van Acker,et al.  A predictive model for substrates of cytochrome P450-debrisoquine (2D6). , 1992, Chemical research in toxicology.

[5]  Yonghua Wang,et al.  A 3-D QSAR Study of Catechol-O-Methyltransferase Inhibitors Using CoMFA and CoMSIA , 2008 .

[6]  R. Cramer,et al.  Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. , 1988, Journal of the American Chemical Society.

[7]  D. Abernethy,et al.  Comparative molecular field analysis of the binding of the stereoisomers of fenoterol and fenoterol derivatives to the beta2 adrenergic receptor. , 2007, Journal of medicinal chemistry.

[8]  M. Sutcliffe,et al.  Why Is Quinidine an Inhibitor of Cytochrome P450 2D6? , 2005, Journal of Biological Chemistry.

[9]  P. Anzenbacher,et al.  Cytochromes P450 and metabolism of xenobiotics , 2001, Cellular and Molecular Life Sciences CMLS.

[10]  K. Burke,et al.  Generalized Gradient Approximation Made Simple [Phys. Rev. Lett. 77, 3865 (1996)] , 1997 .

[11]  A. Hollman.  Quinine and quinidine. , 1991, British heart journal.

[12]  G. Klebe,et al.  Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. , 1994, Journal of medicinal chemistry.

[13]  Frank E. Blaney,et al.  Crystal Structure of Human Cytochrome P450 2D6* , 2005, Journal of Biological Chemistry.

[14]  Magnus Ingelman-Sundberg,et al.  Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. , 2004, Trends in pharmacological sciences.

[15]  Ajay N. Jain.  Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine. , 2003, Journal of medicinal chemistry.