posted on 2014-10-27, 00:00authored byJadel
M. Kratz, Daniela Schuster, Michael Edtbauer, Priyanka Saxena, Christina E. Mair, Julia Kirchebner, Barbara Matuszczak, Igor Baburin, Steffen Hering, Judith M. Rollinger
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.