title: Defining candidate drug characteristics for Long-QT (LQT3) syndrome.
abstract: Mutations of the SCN5A gene can significantly alter the function of cardiac myocyte sodium channels leading to increased risk of ventricular arrhythmia. Over the past decade, detailed Markov models of the action potential of cardiac cells have been developed. In such models, the effects of a drug can be treated as alterations in on- and off rates between open and inactivated states on one hand, and blocked states on the other hand. Our aim is to compute the rates specifying a drug in order to: (a) restore the steady-state open probability of the mutant channel to that of normal wild type channels; and (b) minimize the difference between whole cell currents in drugged mutant and wild type cells. The difference in the electrochemical state vector of the cell can be measured in a norm taking all components and their dynamical properties into account. Measured with this norm, the difference between the state of the mutant and wild-type cell was reduced by a factor of 36 after the drug was introduced and by factors of 4 over mexitiline and 25 over lidocaine. The results suggest the potential to synthesize more effective drugs based on mechanisms of action of existing compounds.
authors.affiliation: Center for Biomedical Computing, Simula Research Laboratory, P.O. Box 134, Lysaker 1325, Norway. aslak@simula.no
authors.forename: Aslak
authors.initials: A
authors.lastname: Tveito
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Lines
authors.forename: Pan
authors.initials: P
authors.lastname: Li
authors.forename: Andrew
authors.initials: A
authors.lastname: McCulloch
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D002462:Cell Membrane / Q000187:drug effects; D003198:Computer Simulation; D015195:Drug Design; D004360:Drug Therapy, Computer-Assisted / Q000379:methods; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000503:physiopathology*; D008564:Membrane Potentials / Q000187:drug effects*; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects*
chemical_list: D018927:Anti-Asthmatic Agents