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

Krisztina Dobi¹  István Hajdú¹  Beáta Flachner¹  Gabriella Fabó¹  Mária Szaszkó¹  Melinda Bognár¹  Csaba Magyar²  István Simon²  Dániel Szisz³  Zsolt Lőrincz¹  Sándor Cseh¹ 

[1] Targetex Ltd., Kápolna köz 4/a., Dunakeszi 2120, Hungary; E-Mails:;Institute of Enzymology, Natural Sciences Research Center, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, Budapest 1117, Hungary; E-Mails:;Chemaxon Ltd., Záhony u. 7, Budapest 1038, Hungary; E-Mail:

关键词: 2D similarity;    3D similarity;    ligand-based virtual screening;    focused library;    phosphodiesterase 4;    phosphodiesterase 5;    flexible alignment;   

DOI  :  10.3390/molecules19067008

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.