title: Discovery of inhibitors of the pentein superfamily protein dimethylarginine dimethylaminohydrolase (DDAH), by virtual screening and hit analysis.
abstract: An efficient process for the discovery of inhibitors of DDAH enzymes, without the requirement for high throughput screening, is described. Physicochemical filtering of a 308,000-compound library according to drug likeness followed by reciprocal nearest neighbour selection produced a representative subset of 35,000 compounds. Virtual screening on a dual processor PC using FlexX, followed by biological screening, identified two hit series. Similarity searches of commercial databases and chemical re-synthesis of pure compounds resulted in SR445 as an inhibitor of Pseudomonas aeruginosa DDAH at 2 microM.
authors.affiliation: Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Basil
authors.initials: B
authors.lastname: Hartzoulakis
authors.forename: Sharon
authors.initials: S
authors.lastname: Rossiter
authors.forename: Herpreet
authors.initials: H
authors.lastname: Gill
authors.forename: Bernard
authors.initials: B
authors.lastname: O'Hara
authors.forename: Emily
authors.initials: E
authors.lastname: Steinke
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gane
authors.forename: Ramon
authors.initials: R
authors.lastname: Hurtado-Guerrero
authors.forename: James M
authors.initials: JM
authors.lastname: Leiper
authors.forename: Patrick
authors.initials: P
authors.lastname: Vallance
authors.forename: Judith Murray
authors.initials: JM
authors.lastname: Rust
authors.forename: David L
authors.initials: DL
authors.lastname: Selwood
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008958:Models, Molecular; D011550:Pseudomonas aeruginosa / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D000581:Amidohydrolases; C059999:dimethylargininase