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Article

Binding of Fidarestat Stereoisomers with Aldose Reductase

by 1,*, 2 and 1,*
1
Systems Microbiology Research Center, KRIBB, Daejeon 305-806, Korea
2
Department of Biomicrosystem Technology, Korea University, Seoul 136-701, Korea
3
Department of Chemical and Biological Engineering, Korea University, Seoul 136-701, Korea
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2006, 7(11), 519-536; https://0-doi-org.brum.beds.ac.uk/10.3390/i7110519
Received: 13 October 2006 / Accepted: 13 November 2006 / Published: 21 November 2006
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. https://0-doi-org.brum.beds.ac.uk/10.3390/i7110519

AMA Style

Kim D, Hong S-I, Lee D-S. Binding of Fidarestat Stereoisomers with Aldose Reductase. International Journal of Molecular Sciences. 2006; 7(11):519-536. https://0-doi-org.brum.beds.ac.uk/10.3390/i7110519

Chicago/Turabian Style

Kim, Dooil, Suk-In Hong, and Dae-Sil Lee. 2006. "Binding of Fidarestat Stereoisomers with Aldose Reductase" International Journal of Molecular Sciences 7, no. 11: 519-536. https://0-doi-org.brum.beds.ac.uk/10.3390/i7110519

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