title: Identification of "toxicophoric" features for predicting drug-induced QT interval prolongation.
abstract: Drugs delaying cardiac repolarization by blockade of hERG K(+) channel generally prolong the QT interval of the electrocardiogram, an effect regarded as a cardiac risk factor with the potential to cause 'torsade des pointes'-type arrhythmias in humans. The present study applied a homology building technique and molecular dynamics simulations to model the pore of hERG K(+) channel. A docking analysis was then performed on selected ligands which were classified as QT-prolonging or non-prolonging after experimental measurements in in vivo anesthetized guinea pig. The results of this structural analysis provided a "toxicophoric" model that was further exploited to inspect a dataset of known QT-prolonging/non-prolonging molecules. The emerging major chemical features to be avoided, in order to obtain cardiac safe therapeutic agents, comprise the simultaneous presence of (i) a protonated nitrogen atom within an observed range of distances from a heteroatom; (ii) aromatic groups capable of interacting within an area defined by Gly657 residues of the pore or within an area located at the top of the longitudinal axis of the pore. Moreover, additional hydrophobic moieties interacting with one of the equatorial cavities located in the area near-by Tyr652 residues and/or with a hydrophobic ring defined by Phe656 residues should be avoided.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Coi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Massarelli
authors.forename: Lara
authors.initials: L
authors.lastname: Testai
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Bianucci
mesh_terms: D000595:Amino Acid Sequence; D006321:Heart / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000071230:Transcriptional Regulator ERG
chemical_list: C072312:ERG protein, human; D021122:Protein Subunits; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG