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.
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.
authors.affiliation: Targetex Ltd., Kápolna köz 4/a., Dunakeszi 2120, Hungary. dobi@targetex.com.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Dobi
authors.affiliation: Targetex Ltd., Kápolna köz 4/a., Dunakeszi 2120, Hungary. hajdu@targetex.com.
authors.forename: István
authors.initials: I
authors.lastname: Hajdú
authors.affiliation: Targetex Ltd., Kápolna köz 4/a., Dunakeszi 2120, Hungary. flachner@targetex.com.
authors.forename: Beáta
authors.initials: B
authors.lastname: Flachner
authors.affiliation: Targetex Ltd., Kápolna köz 4/a., Dunakeszi 2120, Hungary. fabo@targetex.com.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fabó
authors.affiliation: Targetex Ltd., Kápolna köz 4/a., Dunakeszi 2120, Hungary. szaszko@targetex.com.
authors.forename: Mária
authors.initials: M
authors.lastname: Szaszkó
authors.affiliation: Targetex Ltd., Kápolna köz 4/a., Dunakeszi 2120, Hungary. bognar@targetex.com.
authors.forename: Melinda
authors.initials: M
authors.lastname: Bognár
authors.affiliation: Institute of Enzymology, Natural Sciences Research Center, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, Budapest 1117, Hungary. magyar.csaba@ttk.mta.hu.
authors.forename: Csaba
authors.initials: C
authors.lastname: Magyar
authors.affiliation: Institute of Enzymology, Natural Sciences Research Center, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, Budapest 1117, Hungary. simon.istvan@ttk.mta.hu.
authors.forename: István
authors.initials: I
authors.lastname: Simon
authors.affiliation: Chemaxon Ltd., Záhony u. 7, Budapest 1038, Hungary. dszisz@chemaxon.com.
authors.forename: Dániel
authors.initials: D
authors.lastname: Szisz
authors.affiliation: Targetex Ltd., Kápolna köz 4/a., Dunakeszi 2120, Hungary. lorincz@targetex.com.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Lőrincz
authors.affiliation: Targetex Ltd., Kápolna köz 4/a., Dunakeszi 2120, Hungary. cseh@targetex.com.
authors.forename: Sándor
authors.initials: S
authors.lastname: Cseh
authors.affiliation: Targetex Ltd., Kápolna köz 4/a., Dunakeszi 2120, Hungary. dorman@targetex.com.
authors.forename: György
authors.initials: G
authors.lastname: Dormán
mesh_terms: D004353:Drug Evaluation, Preclinical; D015394:Molecular Structure; D058988:Phosphodiesterase 4 Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D013329:Structure-Activity Relationship
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D058986:Phosphodiesterase 5 Inhibitors