Potassium channel, hERG inhibition

CoMSIA (comparative molecular similarity index analysis) is a recent development from CoMFA and does not suffer from the alignment problem. It has been used to model hERG potassium channel inhibition by drugs [59] and the toxicity of phenylsulfonyl carboxylates [60], organophosphates [61], and polybrominated diphenyl ethers [62], with results comparable to those from CoMFA. 

Dearden JC, Netzeva TI. QSAR modelling of hERG potassium channel inhibition with low-dimensional descriptors. I Pharm Pharmacol 2004 56 Suppl S-82. 

Pearlstein RA, Vaz Rl, Kang J, Chen X-L, Preobrazhenskaya M, Shchekotikhin AE et al. Characterisation of HERG Potassium channel inhibition using COMSiA 3D QSAR and homology modeling approaches. Bioorg Med Chem Lett 2003 13 1829-35. 

Sun, H. Liu, X. Xiong, Q. Shikano, S. Li, M. Chronic inhibition of cardiac Kir2.1 and hERG potassium channel by celastrol with dual effects on both ion conductivity and protein trafficking. J. Biol. Chem. 2006, 281, 5877-5884. 

Several studies support the notion that the basic mechanism by which many drugs prolong the QT interval is related to blockade of potassium currents. For instance, several antihistamines, antibacterial macrolides, fluoroquinolones and antipsychotics were shown to inhibit the rapid component of the delayed rectifier K+ current (fKr) in electrophysiological studies and to block potassium channels encoded by hERG [37-42]. 

Paul, A.A., Witchel, H.J. and Hancox, J. C. (2001) Inhibition of HERG potassium channel current by the class la antiarrhythmic agent disopyramide. Biochemical and Biophysical Research Communications, 280, 1243—1250. 

Yoshida, K. and Niwa, T. (2006) Quantitative structure-activity relationship studies on inhibition of HERG potassium channels. Journal of Chemical Information and Modeling, 46, 1371-1378. 

Dorn, A., Hermann, F., Ebneth, A., Bothmann, H., Trube, G., Christensen, K. and Apfel, C. (2005) Evaluation of a high-throughput fluorescence assay method for hERG potassium channel inhibition. Journal of Biomolecular Screening, 10, 339-347. 

Shchekotikhin, A. E., Korolev, A. M., Lysenkova, L. N., Miroshnikova, . V., Hendrix, J., Rampc, D. (2003) Characterization of HERG potassium channel inhibition using CoM-SiA 3D QSAR and homology modeling approaches. Bioorp Med Cbem Lett 13, 1829-1835. 

The most common mechanism of dysrhythmias at the molecular level is by inhibition of the potassium channels known as IK, which are encoded by the human ether-a-go-go-related gene (HERG). The antidysrhythmic drugs that affect these channels include almokalant, amiodar-one, azimilide, bretylium, dofetilide, ibutilide, sematilide, D-sotalol, and tedisamil (all drugs with Class III actions) and bepridil, disopyramide, prenylamine, procainamide, propafenone, quinidine, and terodiline (all drugs with Qass I actions). Other drugs that affect these channels but are not used to treat cardiac dysrhythmias include astemizole and terfenadine (antihistamines), cisapride, erythromycin, haloperidol, sertindole, and thioridazine. 

Kirsch GE, Trepakova ES, Brimecombe JC, et al. Variability in the measurement of hERG potassium channel inhibition Effects of temperature and stimulus pattern. / Pharmacol Toxicol Methods. 2004 50(2) 93-101. 

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