Article

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.

Department of Medicinal Chemistry, Monash University,Vic 3052, Australia.
Journal of Medicinal Chemistry (impact factor: 5.25). 04/2008; 51(5):1478-81. DOI:10.1021/jm701514k pp.1478-81
Source: PubMed

ABSTRACT 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.

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Keywords

1'-position nitrogen
 
2 S4 R stereoisomer
 
catalytic His110
 
cyclic imide ring
 
experimental evidence
 
inhibition mechanism
 
N2 atom
 
potent inhibitor Fidarestat