Determination of hERG channel blockers using a decision tree

Bioorganic & Medicinal Chemistry
Michael M Gepp, Michael C Hutter

Abstract

A decision tree approach for the in silico prediction of Torsade de Pointes (TdP)-causing drugs is presented. As TdP is frequently associated with QT-interval prolongation due to inhibition of the rapid activating delayed rectifier potassium channel in the heart (hERG channel), the properties of such blockers were investigated by molecular modeling and semi-empirical AM1 molecular orbital calculations. In addition, we derived a pharmacophoric SMARTS string using structural information from high affinity compounds. A corresponding search in the PubChem database identified several compounds that exhibit QT-interval prolonging activity that were not among our data set. This SMARTS string furthermore showed to be the most significant descriptor in the decision tree approach from which guidelines for the design of safe compounds are suggested.

References

May 31, 2002·Nature·Youxing JiangRoderick MacKinnon
May 31, 2003·Nature Reviews. Drug Discovery·Bernard Fermini, Anthony A Fossa
Feb 19, 2005·Drug Discovery Today·Alex M Aronov
Mar 8, 2005·Trends in Pharmacological Sciences·Michael C Sanguinetti, John S Mitcheson
Jun 7, 2005·Expert Opinion on Drug Safety·Martin Traebert, Berengere Dumotier

❮ Previous
Next ❯

Citations

May 31, 2012·Journal of Chemical Information and Modeling·Bo-Han SuYufeng J Tseng
Sep 20, 2012·Journal of Chemical Information and Modeling·Serdar DurdagiSergei Y Noskov
Aug 16, 2013·Journal of Chemical Information and Modeling·Paul Czodrowski
Mar 4, 2008·SAR and QSAR in Environmental Research·O FilzV Poroikov
Sep 10, 2013·BMC Pharmacology & Toxicology·Ahmed E EnayetallahMathew T Pletcher
May 15, 2010·Expert Opinion on Drug Metabolism & Toxicology·Anthony E Klon
Jul 4, 2009·Expert Opinion on Drug Metabolism & Toxicology·Emanuel RaschiMaurizio Recanatini
Mar 17, 2015·Advanced Drug Delivery Reviews·Bruno O Villoutreix, Olivier Taboureau
Mar 11, 2008·Journal of Molecular Graphics & Modelling·Shane Weaver, M Paul Gleeson
Oct 11, 2008·Chemical Biology & Drug Design·Khac-Minh Thai, Gerhard F Ecker
Mar 3, 2007·Biochemical and Biophysical Research Communications·Lupei DuLin Xia
Apr 30, 2015·Future Medicinal Chemistry·Yankang JingIstvan J Enyedy
Jun 29, 2007·Bioorganic & Medicinal Chemistry·Stephen R JohnsonPaul Levesque
Jul 1, 2014·Acta Pharmacologica Sinica·Li-li LiuKai-xian Chen
Jun 29, 2018·Future Medicinal Chemistry·Michael C Hutter
Jan 14, 2020·Journal of Medicinal Chemistry·Ziyi YangDongsheng Cao
May 13, 2009·Journal of Chemical Information and Modeling·Britta Nisius, Andreas H Göller

❮ Previous
Next ❯

Related Concepts

Related Feeds

Arrhythmia

Arrhythmias are abnormalities in heart rhythms, which can be either too fast or too slow. They can result from abnormalities of the initiation of an impulse or impulse conduction or a combination of both. Here is the latest research on arrhythmias.

Antipsychotic Drugs

Antipsychotic drugs are a class of medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia and bipolar disorder. Discover the latest research on antipsychotic drugs here