title: Predictive model for L-type channel inhibition: multichannel block in QT prolongation risk assessment.
abstract: Evaluation of the proarrhythmic potential of an investigated compound is now an integral element of the safety profile required for the approval of new drugs. The human ether-à-go-go-related gene (hERG) channel blocking potency is regarded as a surrogate marker of the proarrhythmic risk at the early stages of the research and development process. However, there is no straight correlation between QT prolongation and TdP occurrence probability, and hERG inhibition potential can be an inadequate predictor of QT prolongation. The L-type calcium channel plays a pivotal role in cardiomyocytes' physiology. Thus the main aim of this study was to develop a predictive model for drug-triggered CaL channel inhibition and also the assessment of drug-multichannel interaction effects on the heart rate-corrected QT interval. The data set, consisting of 123 records describing in vitro experimental settings, measured IC₅₀ values and calculated physico-chemical properties for 72 various chemicals, was collected. The models were tested in a modified 10-fold cross-validation procedure. The generalization ability of the best model was as follows: root mean squared error (RMSE) = 1.10, normalized root mean squared error (NRMSE) = 16.09%. Out of the 10 most important variables, 5 described conditions of the in vitro experiments thus their description and experiment's conditions standardization might be the key to the models better performance. The simulations performed with the ToxComp system showed that the hERG block alone causes concentration-dependent QT prolongation, whereas when multichannel block is regarded, the effect could be reversed. For that reason, the multichannel interaction of tested compounds should be taken into consideration, in order to make the proarrhythmic risk assessment more reliable.
authors: Unit of Pharmacoepidemiology and Pharmacoeconomics, Faculty of Pharmacy, Medical College, Jagiellonian University, Cracow, Poland. bbielska@cm-uj.krakow.pl
authors: Barbara
authors: B
authors: Wiśniowska
authors: Aleksander
authors: A
authors: Mendyk
authors: Kamil
authors: K
authors: Fijorek
authors: Anna
authors: A
authors: Glinka
authors: Sebastian
authors: S
authors: Polak
mesh_terms: D001185:Artificial Intelligence; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D019295:Computational Biology; D003198:Computer Simulation; D015507:Drugs, Investigational / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D005103:Expert Systems; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D018570:Risk Assessment / Q000379:methods; D051637:Shaker Superfamily of Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D016171:Torsades de Pointes / Q000139:chemically induced*; D061567:Voltage-Gated Sodium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D015507:Drugs, Investigational; D051638:Ether-A-Go-Go Potassium Channels; C431140:KCNA7 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D026902:Potassium Channel Blockers; C568320:SCN5A protein, human; D051637:Shaker Superfamily of Potassium Channels; D061567:Voltage-Gated Sodium Channel Blockers