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Int. J. Mol. Sci. 2006, 7(11), 519-536; doi:10.3390/i7110519

Binding of Fidarestat Stereoisomers with Aldose Reductase

Systems Microbiology Research Center, KRIBB, Daejeon 305-806, Korea
Department of Biomicrosystem Technology, Korea University, Seoul 136-701, Korea
Department of Chemical and Biological Engineering, Korea University, Seoul 136-701, Korea
Authors to whom correspondence should be addressed.
Received: 13 October 2006 / Accepted: 13 November 2006 / Published: 21 November 2006
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The stereospecificity in binding to aldose reductase (ALR2) of two fidarestat {6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carboxamide} stereoisomers [(2S,4S)and (2R,4S)] has been investigated by means of molecular dynamics simulations using freeenergy integration techniques. The difference in the free energy of binding was found to be2.0 ± 1.7 kJ/mol in favour of the (2S,4S)-form, in agreement with the experimentalinhibition data. The relative mobilities of the fidarestats complexed with ALR2 indicate alarger entropic penalty for hydrophobic binding of (2R,4S)-fidarestat compared to (2S,4S)-fidarestat, partially explaining its lower binding affinity. The two stereoisomers differmainly in the orientation of the carbamoyl moiety with respect to the active site and rotationof the bond joining the carbamoyl substituent to the ring. The detailed structural andenergetic insights obtained from out simulations allow for a better understanding of thefactors determining stereospecific inhibitor-ALR2 binding in the EPF charges model. View Full-Text
Keywords: Aldose reductase; Fidarestat; Stereospecificity; Molecular dynamics; Free energy. Aldose reductase; Fidarestat; Stereospecificity; Molecular dynamics; Free energy.

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MDPI and ACS Style

Kim, D.; Hong, S.-I.; Lee, D.-S. Binding of Fidarestat Stereoisomers with Aldose Reductase. Int. J. Mol. Sci. 2006, 7, 519-536.

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