Pharmacophore-based identification of novel hERG channel blockers of natural origin – Development of a virtual screening workflow and experimental validation

The human ether-a-go-go-related gene (hERG) channel plays a critical role in cardiac action potential repolarization. hERG block can lead to arrhythmia and increased incidence of sudden death. Although several drugs have been removed from the market for this reason, it has just recently been of interest to assess the potential cardiotoxic risks of botanicals. The goal of this study was to design, experimentally validate and apply a virtual screening workflow to identify novel hERG channel blockers, with focus on the investigation of natural products. A ligand-based pharmacophore model collection was developed and theoretically evaluated against databases of known hERG blockers (ChEMBL) and drug-like decoys (WDI). The seven most complementary and suitable models were then used for virtual screening of in-house and commercially available compound libraries. Fifty chemically diverse compounds, including natural products, were selected from the hitlists for bioactivity testing on Xenopus laevis oocytes, using a voltage clamp technique. Cells were treated with 30µM solutions of the compounds, and 30% reduction of the peak tail hERG current was defined as the cut-off for positive blockade. This campaign identified twenty hERG blockers showing an inhibition between 32 and 79%. In summary, we have demonstrated that our virtual screening approach was successful in identifying novel hERG blockers. These experimentally validated models represent a valuable predictive tool in the assessment of potentially cardiotoxic natural compounds incorporated into a international Marie Curie project aiming at target-oriented identification and isolation of hERG channel blockers from highly consumed botanicals.

Acknowledgements:

Work supported by a Marie Curie International Research Staff Exchange Scheme Fellowship within the 7th European Community Framework Programme (hERGscreen). DS thanks UIBK for her position in the Erika Cremer Habilitation Program.