High-resolution structures of human aldose reductase holoenzyme in complex with stereoisomers of the potent inhibitor Fidarestat: stereospecific interaction between the enzyme and a cyclic imide type inhibitor.

Article Details

Citation Copy to clipboard

El-Kabbani O, Darmanin C, Oka M, Schulze-Briese C, Tomizaki T, Hazemann I, Mitschler A, Podjarny A

J Med Chem. 2004 Aug 26;47(18):4530-7.

PubMed ID

15317464 [ View in PubMed

]

Abstract

Structure determinations of human aldose reductase holoenzyme in complex with the 2S4R-,2R4S- and 2R4R-isomers of the potent inhibitor Fidarestat ((2S,4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazoline]-2-carboxamide) were carried out in order to elucidate the binding modes responsible for the differences in their inhibitory potencies. In the complex structure with the 2R4S-isomer the cyclic imide moiety formed hydrogen bonds with the side-chains of Trp111, Tyr48 and His110. In the attempt to determine the complex structure with the least potent 2R4R-isomer this ligand was not observed, and instead, the active site was simultaneously occupied by two citrate molecules (occupancies of 60% and 40%). In the case of 2S4R, the active site was occupied by a citrate molecule which anchors the 2S4R-isomer from its carbamoyl group. The structures of the complexes suggest that the differences in the interactions between the cyclic imide rings and carbamoyl groups of the compounds with residues His110, Trp111, Trp219 and Cys298 account for differences in their inhibitory potencies.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(S,R)-fidarestat	Aldose reductase	IC 50 (nM)	30	N/A	N/A	Details
(S,R)-fidarestat	Aldose reductase	IC 50 (nM)	570	N/A	N/A	Details
(S,R)-fidarestat	Aldose reductase	IC 50 (nM)	11000	N/A	N/A	Details
(S,R)-fidarestat	Aldose reductase	IC 50 (nM)	40000	N/A	N/A	Details