Structure-based optimization and biological evaluation of human 20α-hydroxysteroid dehydrogenase (AKR1C1) salicylic acid-based inhibitors

O El-Kabbani, PJ Scammells, T Day, U Dhagat…

Index: El-Kabbani, Ossama; Scammells, Peter J.; Day, Tom; Dhagat, Urmi; Endo, Satoshi; Matsunaga, Toshiyuki; Soda, Midori; Hara, Akira European Journal of Medicinal Chemistry, 2010 , vol. 45, # 11 p. 5309 - 5317

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Citation Number: 8

Abstract

The tertiary structure of the Leu308Val mutant of human 20α-hydroxysteroid dehydrogenase (AKR1C1) in complex with the inhibitor 3, 5-dichlorosalicylic acid (DCL) has been determined. Structures and kinetic properties of the wild-type and mutant enzymes indicate that Leu308 is a selectivity determinant for inhibitor binding. The Leu308Val mutation resulted in 13-fold and 3-fold reductions in the inhibitory potencies of DCL and 3-bromo-5- ...

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