Experimentally
Validated hERG Pharmacophore Models
as Cardiotoxicity Prediction Tools
Jadel
M. Kratz
Daniela Schuster
Michael Edtbauer
Priyanka Saxena
Christina E. Mair
Julia Kirchebner
Barbara Matuszczak
Igor Baburin
Steffen Hering
Judith M. Rollinger
10.1021/ci5001955.s001
https://acs.figshare.com/articles/journal_contribution/Experimentally_Validated_hERG_Pharmacophore_Models_as_Cardiotoxicity_Prediction_Tools/2241511
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
IC<sub>50</sub> values ranging from 0.13 to 2.77 μM, attesting
to the suitability of the models as cardiotoxicity prediction tools
in a preclinical stage.
2014-10-27 00:00:00
screening workflow
2.77 μ M
bioactivity assessment
50 compounds
IC 50 values
Cardiotoxicity Prediction ToolsThe goal
HEK 293 cells
hERG channel
novel hERG channel blockers
drug development
cardiotoxicity prediction tools
cardiotoxic risks
model
compound libraries
hERG channels
Validated hERG Pharmacophore Models