Combination of Pharmacophore Matching, 2D Similarity Search, and In Vitro Biological Assays in the Selection of Potential 5-HT6 Antagonists from Large Commercial Repositories

• Published in: Chemical biology & drug design Vol. 86; no. 4; pp. 864 - 880
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-10-2015
• Subjects: biological screening; combinatorial chemistry; Databases, Pharmaceutical; drug discovery; Drug Discovery - methods; G-Protein coupled receptor; Humans; Ligands; Models, Molecular; Receptors, Serotonin - metabolism; Serotonin Antagonists - chemistry; Serotonin Antagonists - pharmacology; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; virtual screening; combinatorial chemistry; drug discovery; virtual screening; G-Protein coupled receptor; biological screening
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12563

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.
A combination of 2D similarity approach and pharmacophore matching was used in selecting potential 5‐HT6 antagonists. Three pharmacophore models were created based on the structure of the reference compounds and the 1st 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 novelty.