Discovery of inhibitors of the pentein superfamily protein dimethylarginine dimethylaminohydrolase (DDAH), by virtual screening and hit analysis

Hartzoulakis, B. et al. (2007) Discovery of inhibitors of the pentein superfamily protein dimethylarginine dimethylaminohydrolase (DDAH), by virtual screening and hit analysis. Bioorganic and Medicinal Chemistry Letters, 17(14), pp. 3953-3956. (doi: 10.1016/j.bmcl.2007.04.095) (PMID:17543521)

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 μM.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Leiper, Professor James
• Authors: Hartzoulakis, B., Rossiter, S., Gill, H., O’Hara, B., Steinke, E., Gane, P. J., Hurtado-Guerrero, R., Leiper, J. M., Vallance, P., Rust, J. M., and Selwood, D. L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Bioorganic and Medicinal Chemistry Letters
• Publisher: Elsevier
• ISSN: 0960-894X
• ISSN (Online): 1464-3405
• Published Online: 03 May 2007