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Computer-aided prediction of QT-prolongation. 2008

O Filz, and A Lagunin, and D Filimonov, and V Poroikov
Institute of Biomedical Chemistry of Rus. Acad. Med. Sci., Moscow, Russia. Olfilz@gmail.com

Drug-induced cardiac arrhythmia is acknowledged as a serious obstacle in successful development of new drugs. Several methods for in silico prediction of acquired long QT syndrome (LQTS) caused by the pharmacological blockade of human hERG K+ channels are discussed in literature. We propose to use the computer program PASS, which estimates the probabilities of about 3000 biological activities, not only for prediction of hERG blockade and QT-prolongation but also for the analysis of indirect mechanisms of these actions. After addition in the PASS training set of 163 compounds with data on QT-Prolongation and re-training, it was shown that accuracy of prediction was 87.1% and 81.8% for hERG blockade and QT-prolongation, respectively. Using computer program PharmaExpert we found that in the predicted biological activity spectra there was a certain correlation between the hERG blockade and some other molecular mechanisms of action. Possible role of 1-phosphatidylinositol-4-phospate 5-kinase, dimethylargininase and progesterone 11 alpha-monooxygenase inhibition in hERG blockade was discussed.

UI MeSH Term Description Entries
D008133 Long QT Syndrome A condition that is characterized by episodes of fainting (SYNCOPE) and varying degree of ventricular arrhythmia as indicated by the prolonged QT interval. The inherited forms are caused by mutation of genes encoding cardiac ion channel proteins. The two major forms are ROMANO-WARD SYNDROME and JERVELL-LANGE NIELSEN SYNDROME. Electrocardiogram QT Prolonged
D005544 Forecasting The prediction or projection of the nature of future problems or existing conditions based upon the extrapolation or interpretation of existing scientific data or by the application of scientific methodology. Futurology,Projections and Predictions,Future,Predictions and Projections
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000465 Algorithms A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. Algorithm
D012984 Software Sequential operating programs and data which instruct the functioning of a digital computer. Computer Programs,Computer Software,Open Source Software,Software Engineering,Software Tools,Computer Applications Software,Computer Programs and Programming,Computer Software Applications,Application, Computer Software,Applications Software, Computer,Applications Softwares, Computer,Applications, Computer Software,Computer Applications Softwares,Computer Program,Computer Software Application,Engineering, Software,Open Source Softwares,Program, Computer,Programs, Computer,Software Application, Computer,Software Applications, Computer,Software Tool,Software, Computer,Software, Computer Applications,Software, Open Source,Softwares, Computer Applications,Softwares, Open Source,Source Software, Open,Source Softwares, Open,Tool, Software,Tools, Software
D051638 Ether-A-Go-Go Potassium Channels A family of voltage-gated potassium channels that are characterized by long N-terminal and C-terminal intracellular tails. They are named from the Drosophila protein whose mutation causes abnormal leg shaking under ether anesthesia. Their activation kinetics are dependent on extracellular MAGNESIUM and PROTON concentration. ERG Potassium Channels,Eag Potassium Channels,Eag-Related Potassium Channels,Ether-A-Go-Go Related Potassium Channels,Eag Related Potassium Channels,Ether A Go Go Potassium Channels,Ether A Go Go Related Potassium Channels,Potassium Channels, ERG,Potassium Channels, Eag,Potassium Channels, Eag-Related,Potassium Channels, Ether-A-Go-Go
D021281 Quantitative Structure-Activity Relationship A quantitative prediction of the biological, ecotoxicological or pharmaceutical activity of a molecule. It is based upon structure and activity information gathered from a series of similar compounds. Structure Activity Relationship, Quantitative,3D-QSAR,QSAR,QSPR Modeling,Quantitative Structure Property Relationship,3D QSAR,3D-QSARs,Modeling, QSPR,Quantitative Structure Activity Relationship,Quantitative Structure-Activity Relationships,Relationship, Quantitative Structure-Activity,Relationships, Quantitative Structure-Activity,Structure-Activity Relationship, Quantitative,Structure-Activity Relationships, Quantitative

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