Integrated Approach Including Docking, MD Simulations, and Network Analysis Highlights the Action Mechanism of the Cardiac hERG Activator RPR260243

hERG is a voltage-gatedpotassium channel involved inthe heartcontraction whose defections are associated with the cardiac arrhythmiaLong QT Syndrome type 2. The activator RPR260243 (RPR) representsa possible candidate to pharmacologically treat LQTS2 because it enhancesthe opening of the channel. However, the molecular detail of its actionmechanism remains quite elusive. Here, we address the problem usinga combination of docking, molecular dynamics simulations, and networkanalysis. We show that the drug preferably binds at the interfacebetween the voltage sensor and the pore, enhancing the canonical activationpath and determining a whole-structure rearrangement of the channelthat slightly impairs inactivation.

Automated summary

hERG is a voltage-gated potassium channel involved in heart contraction and its defects are associated with Long QT Syndrome type 2. The drug RPR260243 has the potential to treat LQTS2 by enhancing the opening of the channel. However, the molecular mechanism of its action is not well understood.