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Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5‐HT 6 Antagonists from Large Commercial Repositories
Author(s) -
Dobi Krisztina,
Flachner Beáta,
Pukáncsik Mária,
Máthé Enikő,
Bognár Melinda,
Szaszkó Mária,
Magyar Csaba,
Hajdú István,
Lőrincz Zsolt,
Simon István,
Fülöp Ferenc,
Cseh Sándor,
Dormán György
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12563
Subject(s) - pharmacophore , selection (genetic algorithm) , similarity (geometry) , computational biology , matching (statistics) , chemistry , in vitro , combinatorial chemistry , stereochemistry , computer science , biology , biochemistry , artificial intelligence , mathematics , image (mathematics) , statistics
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‐ HT 6 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.