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Combination of 2D/3D Ligand-Based Similarity Search in Rapid Virtual Screening from Multimillion Compound Repositories. Selection and Biological Evaluation of Potential PDE4 and PDE5 Inhibitors

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 f...

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Detalles Bibliográficos
Autores principales: Dobi, Krisztina, Hajdú, István, Flachner, Beáta, Fabó, Gabriella, Szaszkó, Mária, Bognár, Melinda, Magyar, Csaba, Simon, István, Szisz, Dániel, Lőrincz, Zsolt, Cseh, Sándor, Dormán, György
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270928/
https://www.ncbi.nlm.nih.gov/pubmed/24879613
http://dx.doi.org/10.3390/molecules19067008
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author Dobi, Krisztina
Hajdú, István
Flachner, Beáta
Fabó, Gabriella
Szaszkó, Mária
Bognár, Melinda
Magyar, Csaba
Simon, István
Szisz, Dániel
Lőrincz, Zsolt
Cseh, Sándor
Dormán, György
author_facet Dobi, Krisztina
Hajdú, István
Flachner, Beáta
Fabó, Gabriella
Szaszkó, Mária
Bognár, Melinda
Magyar, Csaba
Simon, István
Szisz, Dániel
Lőrincz, Zsolt
Cseh, Sándor
Dormán, György
author_sort Dobi, Krisztina
collection PubMed
description 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 by various 2D/3D chemoinformatics tools. We report here a combination of the 2D approach with a ligand-based 3D method (Screen3D) which applies flexible matching to align reference and target compounds in a dynamic manner and thus to assess their structural and conformational similarity. In the first case study we compared the 2D and 3D similarity scores on an existing dataset derived from the biological evaluation of a PDE5 focused library. Based on the obtained similarity metrices a fusion score was proposed. The fusion score was applied to refine the 2D similarity search in a second case study where we aimed at selecting and evaluating a PDE4B focused library. The application of this fused 2D/3D similarity measure led to an increase of the hit rate from 8.5% (1st round, 47% inhibition at 10 µM) to 28.5% (2nd round at 50% inhibition at 10 µM) and the best two hits had 53 nM inhibitory activities.
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spelling pubmed-62709282018-12-21 Combination of 2D/3D Ligand-Based Similarity Search in Rapid Virtual Screening from Multimillion Compound Repositories. Selection and Biological Evaluation of Potential PDE4 and PDE5 Inhibitors Dobi, Krisztina Hajdú, István Flachner, Beáta Fabó, Gabriella Szaszkó, Mária Bognár, Melinda Magyar, Csaba Simon, István Szisz, Dániel Lőrincz, Zsolt Cseh, Sándor Dormán, György Molecules Article 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 by various 2D/3D chemoinformatics tools. We report here a combination of the 2D approach with a ligand-based 3D method (Screen3D) which applies flexible matching to align reference and target compounds in a dynamic manner and thus to assess their structural and conformational similarity. In the first case study we compared the 2D and 3D similarity scores on an existing dataset derived from the biological evaluation of a PDE5 focused library. Based on the obtained similarity metrices a fusion score was proposed. The fusion score was applied to refine the 2D similarity search in a second case study where we aimed at selecting and evaluating a PDE4B focused library. The application of this fused 2D/3D similarity measure led to an increase of the hit rate from 8.5% (1st round, 47% inhibition at 10 µM) to 28.5% (2nd round at 50% inhibition at 10 µM) and the best two hits had 53 nM inhibitory activities. MDPI 2014-05-28 /pmc/articles/PMC6270928/ /pubmed/24879613 http://dx.doi.org/10.3390/molecules19067008 Text en © 2014 by the authors. licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Dobi, Krisztina
Hajdú, István
Flachner, Beáta
Fabó, Gabriella
Szaszkó, Mária
Bognár, Melinda
Magyar, Csaba
Simon, István
Szisz, Dániel
Lőrincz, Zsolt
Cseh, Sándor
Dormán, György
Combination of 2D/3D Ligand-Based Similarity Search in Rapid Virtual Screening from Multimillion Compound Repositories. Selection and Biological Evaluation of Potential PDE4 and PDE5 Inhibitors
title Combination of 2D/3D Ligand-Based Similarity Search in Rapid Virtual Screening from Multimillion Compound Repositories. Selection and Biological Evaluation of Potential PDE4 and PDE5 Inhibitors
title_full Combination of 2D/3D Ligand-Based Similarity Search in Rapid Virtual Screening from Multimillion Compound Repositories. Selection and Biological Evaluation of Potential PDE4 and PDE5 Inhibitors
title_fullStr Combination of 2D/3D Ligand-Based Similarity Search in Rapid Virtual Screening from Multimillion Compound Repositories. Selection and Biological Evaluation of Potential PDE4 and PDE5 Inhibitors
title_full_unstemmed Combination of 2D/3D Ligand-Based Similarity Search in Rapid Virtual Screening from Multimillion Compound Repositories. Selection and Biological Evaluation of Potential PDE4 and PDE5 Inhibitors
title_short Combination of 2D/3D Ligand-Based Similarity Search in Rapid Virtual Screening from Multimillion Compound Repositories. Selection and Biological Evaluation of Potential PDE4 and PDE5 Inhibitors
title_sort combination of 2d/3d ligand-based similarity search in rapid virtual screening from multimillion compound repositories. selection and biological evaluation of potential pde4 and pde5 inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270928/
https://www.ncbi.nlm.nih.gov/pubmed/24879613
http://dx.doi.org/10.3390/molecules19067008
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