title: An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment.
abstract: Cell lines expressing ion channels (IC) and the advent of plate-based electrophysiology device have enabled a molecular understanding of the action potential (AP) as a means of early QT assessment. We sought to develop an in silico AP (isAP) model that provides an assessment of the effect of a compound on the myocyte AP duration (APD) using concentration-effect curve data from a panel of five ICs (hNav1.5, hCav1.2, hKv4.3/hKChIP2.2, hKv7.1/hminK, hKv11.1). A test set of 53 compounds was selected to cover a range of selective and mixed IC modulators that were tested for their effects on optically measured APD. A threshold of >10% change in APD at 90% repolarization (APD(90)) was used to signify an effect at the top test concentration. To capture the variations observed in left ventricular midmyocardial myocyte APD data from 19 different dogs, the isAP model was calibrated to produce an ensemble of 19 model variants that could capture the shape and form of the APs and also quantitatively replicate dofetilide- and diltiazem-induced APD(90) changes. Provided with IC panel data only, the isAP model was then used, blinded, to predict APD(90) changes greater than 10%. At a simulated concentration of 30 μM and based on a criterion that six of the variants had to agree, isAP prediction was scored as showing greater than 80% predictivity of compound activity. Thus, early in drug discovery, the isAP model allows integrating separate IC data and is amenable to the throughput required for use as a virtual screen.
authors.affiliation: Computational Biology, Discovery Sciences, Safety Assessment United Kingdom, AstraZeneca R&D, Macclesfield, United Kingdom.
authors.forename: M R
authors.initials: MR
authors.lastname: Davies
authors.forename: H B
authors.initials: HB
authors.lastname: Mistry
authors.forename: L
authors.initials: L
authors.lastname: Hussein
authors.forename: C E
authors.initials: CE
authors.lastname: Pollard
authors.forename: J-P
authors.initials: JP
authors.lastname: Valentin
authors.forename: J
authors.initials: J
authors.lastname: Swinton
authors.forename: N
authors.initials: N
authors.lastname: Abi-Gerges
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects; D002138:Calibration; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000633:toxicity*; D003198:Computer Simulation; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D000072237:ERG1 Potassium Channel; D004567:Electrodes, Implanted; D055724:Electrophysiological Phenomena; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005260:Female; D005453:Fluorescence; D005456:Fluorescent Dyes; D006321:Heart / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D018570:Risk Assessment; D020711:Threshold Limit Values
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002317:Cardiovascular Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005456:Fluorescent Dyes; C419385:L-type calcium channel alpha(1C); D026902:Potassium Channel Blockers