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Molecules 2014, 19(6), 7008-7039; doi:10.3390/molecules19067008

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

1
Targetex Ltd., Kápolna köz 4/a., Dunakeszi 2120, Hungary
2
Institute of Enzymology, Natural Sciences Research Center, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, Budapest 1117, Hungary
3
Chemaxon Ltd., Záhony u. 7, Budapest 1038, Hungary
*
Author to whom correspondence should be addressed.
Received: 25 March 2014 / Revised: 21 May 2014 / Accepted: 22 May 2014 / Published: 28 May 2014
(This article belongs to the Special Issue In-Silico Drug Design and In-Silico Screening)
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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 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. View Full-Text
Keywords: 2D similarity; 3D similarity; ligand-based virtual screening; focused library; phosphodiesterase 4; phosphodiesterase 5; flexible alignment 2D similarity; 3D similarity; ligand-based virtual screening; focused library; phosphodiesterase 4; phosphodiesterase 5; flexible alignment
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Dobi, K.; Hajdú, I.; Flachner, B.; Fabó, G.; Szaszkó, M.; Bognár, M.; Magyar, C.; Simon, I.; Szisz, D.; Lőrincz, Z.; Cseh, S.; Dormán, G. 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. Molecules 2014, 19, 7008-7039.

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