title: Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5-HT6 Antagonists from Large Commercial Repositories.
abstract: Rapid in silico selection of target-focused libraries from commercial repositories is an attractive and cost-effective approach. If structures of active compounds are available, rapid 2D similarity search can be performed on multimillion compound databases, but the generated library requires further focusing. We report here a combination of the 2D approach with pharmacophore matching which was used for selecting 5-HT6 antagonists. In the first screening round, 12 compounds showed >85% antagonist efficacy of the 91 screened. For the second-round (hit validation) screening phase, pharmacophore models were built, applied, and compared with the routine 2D similarity search. Three pharmacophore models were created based on the structure of the reference compounds and the first-round hit compounds. The pharmacophore search resulted in a high hit rate (40%) and led to novel chemotypes, while 2D similarity search had slightly better hit rate (51%), but lacking the novelty. To demonstrate the power of the virtual screening cascade, ligand efficiency indices were also calculated and their steady improvement was confirmed.
authors.affiliation: Targetex Kft., Kápolna köz 4/a, Dunakeszi, H-2120, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Dobi
authors.affiliation: Targetex Kft., Kápolna köz 4/a, Dunakeszi, H-2120, Hungary.
authors.forename: Beáta
authors.initials: B
authors.lastname: Flachner
authors.affiliation: Targetex Kft., Kápolna köz 4/a, Dunakeszi, H-2120, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Pukáncsik
authors.affiliation: Targetex Kft., Kápolna köz 4/a, Dunakeszi, H-2120, Hungary.
authors.forename: Enikő
authors.initials: E
authors.lastname: Máthé
authors.affiliation: Targetex Kft., Kápolna köz 4/a, Dunakeszi, H-2120, Hungary.
authors.forename: Melinda
authors.initials: M
authors.lastname: Bognár
authors.affiliation: Targetex Kft., Kápolna köz 4/a, Dunakeszi, H-2120, Hungary.
authors.forename: Mária
authors.initials: M
authors.lastname: Szaszkó
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2., Budapest, H-1117, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Magyar
authors.affiliation: Targetex Kft., Kápolna köz 4/a, Dunakeszi, H-2120, Hungary.|Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2., Budapest, H-1117, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Hajdú
authors.affiliation: Targetex Kft., Kápolna köz 4/a, Dunakeszi, H-2120, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Lőrincz
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2., Budapest, H-1117, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Simon
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6., Szeged, H-6720, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Fülöp
authors.affiliation: Targetex Kft., Kápolna köz 4/a, Dunakeszi, H-2120, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Cseh
authors.affiliation: Targetex Kft., Kápolna köz 4/a, Dunakeszi, H-2120, Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Dormán
mesh_terms: D062313:Databases, Pharmaceutical; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D008024:Ligands; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D054852:Small Molecule Libraries; C097216:serotonin 6 receptor
keywords: G-Protein coupled receptor; biological screening; combinatorial chemistry; drug discovery; virtual screening