title: Experimentally validated HERG pharmacophore models as cardiotoxicity prediction tools.
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.
authors.affiliation: Departamento de Ciências Farmacêuticas, Universidade Federal de Santa Catarina , 88.040-900 Florianópolis, Santa Catarina, Brazil.
authors.forename: Jadel M
authors.initials: JM
authors.lastname: Kratz
authors.forename: Daniela
authors.initials: D
authors.lastname: Schuster
authors.forename: Michael
authors.initials: M
authors.lastname: Edtbauer
authors.forename: Priyanka
authors.initials: P
authors.lastname: Saxena
authors.forename: Christina E
authors.initials: CE
authors.lastname: Mair
authors.forename: Julia
authors.initials: J
authors.lastname: Kirchebner
authors.forename: Barbara
authors.initials: B
authors.lastname: Matuszczak
authors.forename: Igor
authors.initials: I
authors.lastname: Baburin
authors.forename: Steffen
authors.initials: S
authors.lastname: Hering
authors.forename: Judith M
authors.initials: JM
authors.lastname: Rollinger
mesh_terms: D001665:Binding Sites; D002316:Cardiotonic Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D015870:Gene Expression; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D002316:Cardiotonic Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D008024:Ligands; D026902:Potassium Channel Blockers; D011994:Recombinant Proteins; D054852:Small Molecule Libraries