title: Combining 2D and 3D in silico methods for rapid selection of potential PDE5 inhibitors from multimillion compounds' repositories: biological evaluation.
abstract: Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost-effective approach when starting new drug discovery projects. If structures of active compounds are available rapid 2D similarity search can be performed on multimillion compounds' databases. This in silico approach can be combined with physico-chemical parameter filtering based on the property space of the active compounds and 3D virtual screening if the structure of the target protein is available. A multi-step virtual screening procedure was developed and applied to select potential phosphodiesterase 5 (PDE5) inhibitors in real time. The combined 2D/3D in silico method resulted in the identification of 14 novel PDE5 inhibitors with <1 μMIC(50) values and the hit rate in the second in silico selection and in vitro screening round exceeded the 20%.
authors.affiliation: TargetEx, Kápolna köz 4/a, Dunakeszi, 2120, Hungary.
authors.forename: Tünde
authors.initials: T
authors.lastname: Tömöri
authors.forename: István
authors.initials: I
authors.lastname: Hajdú
authors.forename: László
authors.initials: L
authors.lastname: Barna
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Lorincz
authors.forename: Sándor
authors.initials: S
authors.lastname: Cseh
authors.forename: György
authors.initials: G
authors.lastname: Dormán
mesh_terms: D000818:Animals; D002460:Cell Line; D019295:Computational Biology / Q000379:methods*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008958:Models, Molecular; D058986:Phosphodiesterase 5 Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D010879:Piperazines / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology; D060066:Protein Interaction Maps; D011687:Purines / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology; D012015:Reference Standards; D000068677:Sildenafil Citrate; D054852:Small Molecule Libraries / Q000032:analysis* / Q000494:pharmacology; D013450:Sulfones / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D054852:Small Molecule Libraries; D013450:Sulfones; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5