The discovery of Kv1.5 blockers as a case study for the application of virtual screening approaches.
Different virtual screening techniques are available as alternatives to high throughput screening. These different techniques have been rarely used together on the same target. We had the opportunity to do so in order to discover novel blockers of the voltage-dependent potassium channel Kv1.5, a potential target for the treatment of atrial fibrillation. Our corporate database was searched, using a protein-based pharmacophore, derived from a homology model, as query. As a result, 244 molecules were screened in vitro, 19 of them (7.8%) were found to be active. Five of them, belonging to five different chemical classes, exhibited IC50 values under 10 microM. The performance of this structure-based virtual screening protocol has been compared with those of similarity and ligand-based pharmacophore searches. The analysis of the results supports the conventional wisdom of using as many virtual screening techniques as possible in order to maximize the chance of finding as many chemotypes as possible.
Pirard
Bernard
B
Aventis Pharma Deutschland GmbH, A Company of the Sanofi-Aventis Group, Computational Chemistry, Medicinal Chemistry, Industrie Park Höchst, Building G878, D-65926 Frankfurt am Main, Germany. bernard.pirard@aventis.com
Brendel
Joachim
J
Peukert
Stefan
S
D000595:Amino Acid Sequence; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D020128:Inhibitory Concentration 50; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008969:Molecular Sequence Data; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D040681:Structural Homology, Protein
D051666:Kv1.5 Potassium Channel; D008024:Ligands; D026902:Potassium Channel Blockers; D021122:Protein Subunits