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Structure and function of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
de Groot et al. (1996) derived a homology model for CYP2D6 on the basis of the structures of bacterial CYP101, CYP102, and CYP108 and incorporating a wide variety of site-directed mutagenesis data concerning the CYP2 family members. The final model consisted of four segments: (a) the B, B′, and C helices and the β1-sheet (Gly66–Lys146); (b) the F and G helices (Leu205–Asp263); (c) the I, J, J′, K, and L helices, the β2-, β3-, β4-, and β5-sheets, and the heme binding domain (Pro286–Arg497); and (d) the heme moiety (de Groot et al. 1996). Three classical CYP2D6 substrates including debrisoquine, dextromethorphan, and GBR-12,909 (vanoxerine, a dopamine reuptake inhibitor) and one potent inhibitor, ajmalicine, are consecutively docked into the active site of the protein model. Amino acids responsible for binding and orientation of the various CYP2D6 substrates and inhibitors are identified: Pro102 and Gln108 (strand leading to the B′ helix, putative substrate recognition site 1 [SRS1]); Arg115, Ser116, Gln117, Leu121, and Ala122 (strand running from the B′ helix, SRS1); Leu213 (F helix, SRS2); Asp301, Ser304, Ala305, and Thr309 (I helix, SRS4); Val370 (K helix, SRS5); Pro371 (′-sheet, SRS5); and Leu484 (′-sheet, SRS6) (de Groot et al. 1996).
Emerging pharmacotherapies for the treatment of atrial fibrillation
Published in Expert Opinion on Emerging Drugs, 2018
Alessandro Capucci, Laura Cipolletta, Federico Guerra, Irene Giannini
Vanoxerine is a dopamine transporter 1 antagonist originally studied for Parkinson disease. Using whole-cell patch clamp techniques, a potent inhibition of the IKr, INa, and ICaL currents has been demonstrated[66]. Interestingly, the degree of channel block is use-dependent for all three ion channels, in particular for INa and ICaL. Therefore, it is selective for atrial tissue, especially during AF, similar to vernakalant. Studies with canine ventricular wedge preparations showed that vanoxerine did not influence the QT interval and the action potential (AP) waveform or the transmural dispersion of repolarization, leading to a low possibility of ventricular arrhythmia induction [68].