HERG

In general, the detection of adverse drug reactions early in the drug discovery process is becoming commonplace. So-called liability panels of receptors, hERG channel activity, and cytochrome enzymes are utilized to identify... 

This minimal K+ channel (MinK) encoded by KCNEl consists of 130 amino acid residues and has a single transmembrane segment. A slowly activating K+ current-induced MinK cRNA is expressed in Xenopus oocytes. Coexpression of KvLQTl with MinK induced a current that has characteristics similar to cardiac slowly activating delayed-rectifier K+ current, DCS, in contrast to DCR that has relative fast activation and is composed of hERG/MiRPl. 

MiRPl KCNE2 21 q22.1 Heart, skeletal muscle hERG Partner to form the cardiac IKR channel LQT6... 

Kv1.5, hERG/MiRP, KvLQT1/MinK Arrhythmia, angina Ambasilide (LU 47710), Tedisamil... 

Congenital Long QT syndrome Human-ether-a-go-go-related protein (HERG) E-4031, astemizole, cisapride... 

Shaker-channels, eag (ether- -go-go)-channels, slo (slow-poke)-channels were cloned from behavioral Drosophila melanogaster mutants. The channels were named according to the Drosophila mutant phenotype, Shaker, ether-go-go, slow-poke. Subsequently, eag-cDNA was used to clone related voltage-gated potassium channel subunits erg (eag-related) and elk (eag-like). The human erg ortholog (HERG) mediates cardiac DCS. 

A particularly interesting example of Kv-channel inactivation is represented by HERG-channels. HERG-channels have faster inactivation than activation kinetics, and they very rapidly recover from inactivation at negative membrane potentials. This behavior may result in a situation where most of the current carried by HERG-channels occurs during their recovery from inactivation at negative potentials, that is, it represents an inward rather than outward current. 

In addition to the membrane-inserted core domain of Kv channels, their cytoplasmic domains have important roles for Kv-channel function [5]. Many of these functions are related to subunits assembly, channel trafficking to and from the plasma membrane, and interactions with cytoskeletal components (Fig. la). A tetramerization (T) domain for subunit assembly has been well defined in Shaker-channels, where it is localized in the amino-terminus. Other Kv-channels (e.g., eag, HERG, KvLQTl) may have comparable domains within the cytoplasmic carboxy-terminus. ER retention and retrieval signals have been found... 

KCNQ-channels, HERG-channels, and Shaker-related Kv-channels. 

Heparin Sulfate Proteoglycans Hepatic Lipase Hepatitis Hepatitis C Heptahelical Domain Heptahelical Receptors HERG-channels Heterologous Desensitization Heterologous Expression System Heterotrimeric G-Proteins Hidden Markov Model High-density Lipoprotein (HDL)... 

Ausgehend von Nitrilen werden N-Athyl-iminium-Derivate I am besten mit dem Tria-thyloxonium-Ion, andere N-Alkyl-Verbindungen mit Dialkoxycarbenium-Ionen herge-stellt2 3. 

Aronov AM, Goldman BB. A model for identifying HERG K+ channel blockers. Bioorg Med Chem 2004 12 2307-37. 

A widely used 3-D QSAR method that makes use of PLS is comparative molecular field analysis (CoMFA), in which a probe atom is used to calculate the steric and electronic fields at numerous points in a 3D lattice within which the molecules have been aligned. Poso et al. [56] used the technique to model the binding of coumarins to cytochrome P450 2A5, with similar results to those obtained by Bravi and Wikel [55]. Shi et al. [57] used it to model the estrogen receptor binding of a large diverse set of compounds, and Cavalli et al. [58] used it to develop a pharmacophore for hERG potassium... 

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. 

Cavalli A, Poluzzi E, De Ponti F, Recanatini M. Toward a pharmacophore for drugs inducing the long QT syndrome insights from a CoMFA study of HERG K channel blockers. / Med Chem 2002 45 3844-53. 

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. 

Aptula AO, Cronin MTD. Prediction of hERG K blocking potency application of structural knowledge. SAR QSAR Environ Res 2004 15 399-411. 

ADMET absorption, distribution, metabolism, excretion and toxicity BLW-ED block-localized wave function energy decomposition hERG human ether-a-go-go-related gene QSAR quantitative structure-activity relationship... 

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