Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 21, Issue 8, Pages 2564-2567Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.01.076
Keywords
Aldo-keto reductase; 3-Chloro-5-phenylsalicylic acid; Cancer; Drug design; Human 20 alpha-hydroxysteroid dehydrogenase
Categories
Funding
- Monash Graduate School postgraduate scholarship
- Japan Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [22590102, 21790245] Funding Source: KAKEN
Ask authors/readers for more resources
Human 20 alpha-hydroxysteroid dehydrogenase (AKR1C1) is an important drug target due to its role in the development of lung and endometrial cancers, premature birth and neuronal disorders. We report the crystal structure of AKR1C1 complexed with the first structure-based designed inhibitor 3-chloro-5-phenylsalicylic acid (K(i) = 0.86 nM) bound in the active site. The binding of 3-chloro-5-phenylsalicylic acid to AKR1C1 resulted in a conformational change in the side chain of Phe311 to accommodate the bulky phenyl ring substituent at the 5-position of the inhibitor. The contributions of the nonconserved residues Leu54, Leu306, Leu308 and Phe311 to the binding were further investigated by site-directed mutagenesis, and the effects of the mutations on the K(i) value were determined. The Leu54Val and Leu306Ala mutations resulted in 6- and 81-fold increases, respectively, in K(i) values compared to the wild-type enzyme, while the remaining mutations had little or no effects. (C) 2011 Published by Elsevier Ltd.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available