Despite the importance of the hERG channel in drug discovery and the sizable number of antagonist molecules discovered, only a few hERG agonists have been discovered. Here we report the discovery of a novel hERG agonist, SKF-32802, as well as SB-335573, a structural analog of the agonist NS3623, discovered through a similarity search of published hERG agonists. SKF-32802 incorporates an amide linker rather than NS3623's urea, resulting in a compound with a different mechanism of action. Both compounds decrease the time constant of open channel kinetics, increase the amplitude of the envelope of tails assay, mildly increase the amplitude of the IV curve, bind the hERG channel in either open or closed states, increase the plateau of the voltage dependence of activation and modulate the effects of the hERG antagonist, quinidine. Interestingly, neither compound affects inactivation nor deactivation kinetics, a property unique among hERG agonists. Additionally, SKF-32802 induces a leftward shift in the voltage dependence of activation. Computational docking studies were conducted to structurally rationalize the observed pharmacology and will be the focus of this presentation.

Use of computational docking studies to rationalize the observed pharmacology of SKF-32802, a novel hERG agonist

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.