Key result
Ligand-based pharmacophore models identified 20 compounds inhibiting hERG channels with IC50 values of 0.13-2.77 μM, validating their use as preclinical cardiotoxicity prediction tools.
The developed ligand-based pharmacophore models successfully identified novel hERG channel blockers, demonstrating their utility as preclinical cardiotoxicity prediction tools.
May inform preclinical hERG screening in drug development; leaves open clinical translation.
The goal of this study was to design, experimentally validate, and apply a virtual screening workflow to identify novel hERG channel blockers. The hERG channel is an important antitarget in drug development since cardiotoxic risks remain as a major cause of attrition. A ligand-based pharmacophore model collection was developed and theoretically validated. The seven most complementary and suitable models were used for virtual screening of in-house and commercially available compound libraries. From the hit lists, 50 compounds were selected for experimental validation through bioactivity assessment using patch clamp techniques. Twenty compounds inhibited hERG channels expressed in HEK 293 cells with IC50 values ranging from 0.13 to 2.77 μM, attesting to the suitability of the models as cardiotoxicity prediction tools in a preclinical stage.
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Kratz et al. (2014) studied Cardiotoxicity. Ligand-based pharmacophore models was evaluated on hERG channel inhibition. Ligand-based pharmacophore models identified 20 compounds inhibiting hERG channels with IC50 values of 0.13-2.77 μM, validating their use as preclinical cardiotoxicity prediction tools.
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