Unusual binding mode of the 2S4R stereoisomer of the potent aldose reductase cyclic imide inhibitor fidarestat (2S4S) in the 15 K crystal structure of the ternary complex refined at 0.78 A resolution: implications for the inhibition mechanism.

Hai-Tao Zhao , Isabelle Hazemann (1) , Andre Mitschler (1) , Vincenzo Carbone , Andrzej Joachimiak , Steve Ginell , Alberto D. Podjarny (1) , Ossama El-Kabbani

1 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

The structure of human aldose reductase in complex with the 2 S4 R stereoisomer of the potent inhibitor Fidarestat ((2 S,4 S)-6-fluoro-2',5'-dioxospiro-[chroman-4,4'-imidazoline]-2-carboxamide) was determined at 15 K and a resolution of 0.78 A. The structure of the complex provides experimental evidence for the inhibition mechanism in which Fidarestat is initially bound neutral and then becomes negatively charged by donating the proton at the 1'-position nitrogen of the cyclic imide ring to the N2 atom of the catalytic His110.

Domaines: Biologie moléculaire

Hai-Tao Zhao, Isabelle Hazemann, Andre Mitschler, Vincenzo Carbone, Andrzej Joachimiak, et al.. Unusual binding mode of the 2S4R stereoisomer of the potent aldose reductase cyclic imide inhibitor fidarestat (2S4S) in the 15 K crystal structure of the ternary complex refined at 0.78 A resolution: implications for the inhibition mechanism.. Journal of Medicinal Chemistry, 2008, 51 (5), pp.1478-81. ⟨10.1021/jm701514k⟩. ⟨hal-00282358⟩