1EF3

FIDARESTAT BOUND TO HUMAN ALDOSE REDUCTASE

Summary for 1EF3

• Entry DOI: 10.2210/pdb1ef3/pdb
• Descriptor: ALDOSE REDUCTASE, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, (2S,4S)-2-AMINOFORMYL-6-FLUORO-SPIRO[CHROMAN-4,4'-IMIDAZOLIDINE]-2',5'-DIONE, ... (4 entities in total)
• Functional Keywords: beta barrel, protein-inhibitor complex, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P15121
• Total number of polymer chains: 2
• Total formula weight: 73579.55

Authors

Oka, M.,Matsumoto, Y.,Sugiyama, S.,Tsuruta, N.,Matsushima, M. (deposition date: 2000-02-06, release date: 2001-02-07, Last modification date: 2023-08-09)

Primary citation

Oka, M.,Matsumoto, Y.,Sugiyama, S.,Tsuruta, N.,Matsushima, M.
A potent aldose reductase inhibitor, (2S,4S)-6-fluoro-2', 5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide (Fidarestat): its absolute configuration and interactions with the aldose reductase by X-ray crystallography.
J.Med.Chem., 43:2479-2483, 2000

PubMed Abstract: The absolute configuration of the aldose reductase (AR) inhibitor, (+)-(2S,4S)-6-fluoro-2',5'-dioxospiro¿chroman-4, 4'-imidazolidine-2-carboxamide (fidarestat), was established indirectly by single-crystal X-ray analysis of (+)-(2S, 4S)-8-bromo-6-fluoro-2',5'-dioxospiro¿chroman-4, 4'-imidazolidine-2-carboxylic acid (1). The crystal structure of human AR complexed with fidarestat was determined, and the specific inhibition activity was discussed on the basis of the three-dimensional interactions between them. The structure clarified that fidarestat was located in the active site by hydrophilic and hydrophobic interactions and that the carbamoyl group of fidarestat was a very effective substituent for affinity to AR and for selectivity between AR and aldehyde reductase (AHR). Explanations for the differences between the observed activities of fidarestat and its stereoisomer 2 were suggested by computer modeling.

PubMed: 10882376
DOI: 10.1021/jm990502r

Experimental method

X-RAY DIFFRACTION (2.8 Å)