Using in silico biology to facilitate drug development.

ABSTRACT

G protein-coupled receptor (GPCR) mediation of cardiac excitability is often overlooked in predicting the likelihood that a compound will alter repolarization. While the areas of GPCR signal transduction and electrophysiology are rich in data, experiments combining the two are difficult. In silico modelling facilitates the integration of all relevant data in both areas to explore the hypothesis that critical associations may exist between the different GPCR signalling mechanisms and cardiac excitability and repolarization. An example of this linkage is suggested by the observation that a mutation of the gene encoding HERG, the pore-forming subunit of the rapidly activating delayed rectifier K+ current (I(Kr)), leads to a form of long QT syndrome in which affected individuals are vulnerable to stress-induced arrhythmia following beta-adrenergic stimulation. Using Physiome's In Silico Cell, we constructed a model integrating the signalling mechanisms of second messengers cAMP and protein kinase A with I(Kr) in a cardiac myocyte. We analysed the model to identify the second messengers that most strongly influence I(Kr) behaviour. Our conclusions indicate that the dynamics of regulation are multifactorial, and that Physiome's approach to in silico modelling helps elucidate the subtle control mechanisms at play.