1. Experimentally validated HERG pharmacophore models as cardiotoxicity prediction tools
- Author
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Daniela Schuster, Igor Baburin, Judith M. Rollinger, Priyanka Saxena, Julia Kirchebner, Michael Edtbauer, Barbara Matuszczak, Steffen Hering, Christina E. Mair, and Jadel M. Kratz
- Subjects
ERG1 Potassium Channel ,Cardiotonic Agents ,Patch-Clamp Techniques ,Computer science ,General Chemical Engineering ,hERG ,Drug Evaluation, Preclinical ,Molecular Conformation ,Gene Expression ,Computational biology ,Library and Information Sciences ,Pharmacology ,Molecular Dynamics Simulation ,Ligands ,Membrane Potentials ,Small Molecule Libraries ,Structure-Activity Relationship ,User-Computer Interface ,High-Throughput Screening Assays ,Potassium Channel Blockers ,Humans ,Virtual screening ,Cardiotoxicity ,Binding Sites ,biology ,General Chemistry ,Ether-A-Go-Go Potassium Channels ,Recombinant Proteins ,Computer Science Applications ,Antitarget ,HEK293 Cells ,Drug development ,Drug Design ,biology.protein ,Pharmacophore ,Preclinical stage ,Protein Binding - Abstract
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.
- Published
- 2014