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

Krisztina Dobi, Beáta Flachner, Mária Pukáncsik, Eniko Máthé, Melinda Bognár, Mária Szaszkõ, C. Magyar, István Hajdú, Zsolt Lorincz, I. Simon, F. Fülöp, S. Cseh, György Dormán

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)864-880
Number of pages17
JournalChemical Biology and Drug Design
Volume86
Issue number4
DOIs
Publication statusPublished - Oct 1 2015

Fingerprint

Biological Assay
Libraries
Assays
Screening
Computer Simulation
Databases
Ligands
Costs and Cost Analysis
In Vitro Techniques
Costs

Keywords

  • biological screening
  • combinatorial chemistry
  • drug discovery
  • G-Protein coupled receptor
  • virtual screening

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Combination of Pharmacophore Matching, 2D Similarity Search, and in Vitro Biological Assays in the Selection of Potential 5-HT6 Antagonists from Large Commercial Repositories. / Dobi, Krisztina; Flachner, Beáta; Pukáncsik, Mária; Máthé, Eniko; Bognár, Melinda; Szaszkõ, Mária; Magyar, C.; Hajdú, István; Lorincz, Zsolt; Simon, I.; Fülöp, F.; Cseh, S.; Dormán, György.

In: Chemical Biology and Drug Design, Vol. 86, No. 4, 01.10.2015, p. 864-880.

Research output: Contribution to journalArticle

Dobi, Krisztina ; Flachner, Beáta ; Pukáncsik, Mária ; Máthé, Eniko ; Bognár, Melinda ; Szaszkõ, Mária ; Magyar, C. ; Hajdú, István ; Lorincz, Zsolt ; Simon, I. ; Fülöp, F. ; Cseh, S. ; Dormán, György. / Combination of Pharmacophore Matching, 2D Similarity Search, and in Vitro Biological Assays in the Selection of Potential 5-HT6 Antagonists from Large Commercial Repositories. In: Chemical Biology and Drug Design. 2015 ; Vol. 86, No. 4. pp. 864-880.
@article{6733095204a2416588fbaf246ab680d7,
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.",
keywords = "biological screening, combinatorial chemistry, drug discovery, G-Protein coupled receptor, virtual screening",
author = "Krisztina Dobi and Be{\'a}ta Flachner and M{\'a}ria Puk{\'a}ncsik and Eniko M{\'a}th{\'e} and Melinda Bogn{\'a}r and M{\'a}ria Szaszk{\~o} and C. Magyar and Istv{\'a}n Hajd{\'u} and Zsolt Lorincz and I. Simon and F. F{\"u}l{\"o}p and S. Cseh and Gy{\"o}rgy Dorm{\'a}n",
year = "2015",
month = "10",
day = "1",
doi = "10.1111/cbdd.12563",
language = "English",
volume = "86",
pages = "864--880",
journal = "Chemical Biology and Drug Design",
issn = "1747-0277",
publisher = "Blackwell",
number = "4",

}

TY - JOUR

T1 - Combination of Pharmacophore Matching, 2D Similarity Search, and in Vitro Biological Assays in the Selection of Potential 5-HT6 Antagonists from Large Commercial Repositories

AU - Dobi, Krisztina

AU - Flachner, Beáta

AU - Pukáncsik, Mária

AU - Máthé, Eniko

AU - Bognár, Melinda

AU - Szaszkõ, Mária

AU - Magyar, C.

AU - Hajdú, István

AU - Lorincz, Zsolt

AU - Simon, I.

AU - Fülöp, F.

AU - Cseh, S.

AU - Dormán, György

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

AB - 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.

KW - biological screening

KW - combinatorial chemistry

KW - drug discovery

KW - G-Protein coupled receptor

KW - virtual screening

UR - http://www.scopus.com/inward/record.url?scp=84942551614&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942551614&partnerID=8YFLogxK

U2 - 10.1111/cbdd.12563

DO - 10.1111/cbdd.12563

M3 - Article

C2 - 25823681

AN - SCOPUS:84942551614

VL - 86

SP - 864

EP - 880

JO - Chemical Biology and Drug Design

JF - Chemical Biology and Drug Design

SN - 1747-0277

IS - 4

ER -