title: Monte Carlo method for predicting of cardiac toxicity: hERG blocker compounds.
abstract: The estimation of the cardiotoxicity of compounds is an important task for the drug discovery as well as for the risk assessment in ecological aspect. The experimental estimation of the above endpoint is complex and expensive. Hence, the theoretical computational methods are very attractive alternative of the direct experiment. A model for cardiac toxicity of 400 hERG blocker compounds (pIC50) is built up using the Monte Carlo method. Three different splits into the visible training set (in fact, the training set plus the calibration set) and invisible validation sets examined. The predictive potential is very good for all examined splits. The statistical characteristics for the external validation set are (i) the coefficient of determination r(2)=(0.90-0.93); and (ii) root-mean squared error s=(0.30-0.40).
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, Laboratory of Pharmacodynamics and Pharmacokinetics, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, Laboratory of Pharmacodynamics and Pharmacokinetics, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milan, Italy.
authors.forename: Marten
authors.initials: M
authors.lastname: Beeg
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, Laboratory of Pharmacodynamics and Pharmacokinetics, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milan, Italy; Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli, 25, 20133 Milan, Italy.
authors.forename: Mariya A
authors.initials: MA
authors.lastname: Toropova
authors.affiliation: Department of Environmental Health Science, Laboratory of Environmental Chemistry and Toxicology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milan, Italy. Electronic address: andrey.toropov@marionegri.it.
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Toropov
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, Laboratory of Biochemistry and Protein Chemistry, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156 Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
mesh_terms: D066126:Cardiotoxicity; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D015233:Models, Statistical; D015394:Molecular Structure; D009010:Monte Carlo Method; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D018570:Risk Assessment; D012984:Software
chemical_list: D000072237:ERG1 Potassium Channel; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers
keywords: CORAL software; Cardiac toxicity; Monte Carlo method; OECD principles; QSAR