REAL

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 and Hajdú, István and Flachner, Beáta and Fabó, Gabriella and Szaszkó, Mária and Bognár, Melinda and Magyar, Csaba and Simon, István and Szisz, Dániel and Lőrincz, Zsolt and Cseh, Sándor and Dormán, György (2014) 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, 19 (6). pp. 7008-7039. ISSN 1420-3049

[img]
Preview
Text
document.pdf

Download (1MB) | Preview

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 microM) to 28.5% (2nd round at 50% inhibition at 10 microM) and the best two hits had 53 nM inhibitory activities.

Item Type: Article
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 25 Jun 2014 11:07
Last Modified: 25 Jun 2014 12:54
URI: http://real.mtak.hu/id/eprint/13339

Actions (login required)

View Item View Item