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Studies by O. Elkabbani and co-authors describe new findings in enzyme research
2009 JUL 27 - (NewsRx.com) -- "The first design, synthesis, and evaluation of human 20(x-hydroxysteroid dehydrogenase (AKR1C1) inhibitors based on the recently published crystal structure of its ternary complex with inhibitor are reported," scientists in Parkville, Australia report. "While the enzyme-inhibitor interactions observed in the crystal structure remain conserved with the newly designed inhibitors, the additional phenyl group of the most potent compound, 3-bromo-5-phenylsalicylic acid, targets a nonconserved hydrophobic pocket in the active site of AKR1C1 resulting in 21-fold improved potency (K-i = 4 nM) over the structurally similar 3 alpha-hydroxysteroid dehydrogenase isoform (AKR1C2). The compound is hydrogen bonded to Tyr55, His 117, and His222, and the phenyl ring forms additional van der Waals interactions with residues Leu308, Phe311, and the nonconserved Leu54 (Val in AKR1C2)," wrote O. Elkabbani and colleagues. The researchers concluded: "Additionally, the metabolism of progesterone in AKR1C1-overexpressed cells was potently inhibited by 3-bromo-5-phenylsalicylic acid, which was effective from 10 nM with an IC50 value equal to 460 nM.." Elkabbani and colleagues published their study in the Journal of Medicinal Chemistry (Structure-Guided Design, Synthesis, and Evaluation of Salicylic Acid-Based Inhibitors Targeting a Selectivity Pocket in the Active Site of Human 20 alpha-Hydroxysteroid Dehydrogenase (AKR1C1). Journal of Medicinal Chemistry, 2009;52(10):3259-3264). For additional information, contact O. Elkabbani, Monash Institute Pharmaceutical Science, 381 Royal Parade, Parkville, Vic 3052, Australia. The publisher's contact information for the Journal of Medicinal Chemistry is: American Chemical Society, 1155 16th St., NW, Washington, DC 20036, USA. Keywords: Australia, Parkville, Dehydrogenase, Enzyme Research, Enzymology, Medicinal Chemistry. This article was prepared by Proteomics Weekly editors from staff and other reports. Copyright 2009, Proteomics Weekly via NewsRx.com.
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