Discovery of inhibitors of the pentein superfamily protein dimethylarginine dimethylaminohydrolase (DDAH), by virtual screening and hit analysis.
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.
Hartzoulakis
Basil
B
Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
Rossiter
Sharon
S
Gill
Herpreet
H
O'Hara
Bernard
B
Steinke
Emily
E
Gane
Paul J
PJ
Hurtado-Guerrero
Ramon
R
Leiper
James M
JM
Vallance
Patrick
P
Rust
Judith Murray
JM
Selwood
David L
DL
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008958:Models, Molecular; D011550:Pseudomonas aeruginosa / Q000201:enzymology*
D004791:Enzyme Inhibitors; D000581:Amidohydrolases; C059999:dimethylargininase