title: Computational investigations of hERG channel blockers: New insights and current predictive models.
abstract: Identification of potential human Ether-a-go-go Related-Gene (hERG) potassium channel blockers is an essential part of the drug development and drug safety process in pharmaceutical industries or academic drug discovery centers, as they may lead to drug-induced QT prolongation, arrhythmia and Torsade de Pointes. Recent reports also suggest starting to address such issues at the hit selection stage. In order to prioritize molecules during the early drug discovery phase and to reduce the risk of drug attrition due to cardiotoxicity during pre-clinical and clinical stages, computational approaches have been developed to predict the potential hERG blockage of new drug candidates. In this review, we will describe the current in silico methods developed and applied to predict and to understand the mechanism of actions of hERG blockers, including ligand-based and structure-based approaches. We then discuss ongoing research on other ion channels and hERG polymorphism susceptible to be involved in LQTS and how systemic approaches can help in the drug safety decision.
authors.affiliation: Molecules Therapeutiques in silico (MTi), Sorbonne Paris Cité, Universite Paris-Diderot, UMR-S 973, 75205 Paris Cedex 13, France; Molecules Therapeutiques in silico (MTi), Sorbonne Paris Cité, INSERM, UMR-S 973, 75205 Paris Cedex 13, France. Electronic address: Bruno.Villoutreix@inserm.fr.
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.affiliation: Molecules Therapeutiques in silico (MTi), Sorbonne Paris Cité, Universite Paris-Diderot, UMR-S 973, 75205 Paris Cedex 13, France; Molecules Therapeutiques in silico (MTi), Sorbonne Paris Cité, INSERM, UMR-S 973, 75205 Paris Cedex 13, France. Electronic address: olivier.taboureau@univ-paris-diderot.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Taboureau
mesh_terms: D000818:Animals; D003198:Computer Simulation; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008133:Long QT Syndrome / Q000139:chemically induced*; D008954:Models, Biological; D026902:Potassium Channel Blockers / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D008024:Ligands; D026902:Potassium Channel Blockers
keywords: Arrhythmia; Computational approaches; Ligand-based; QSAR; Structure based, Polymorphism; TdP; hERG