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Title 

Binding of fidarestat stereoisomers with aldose reductase

Authors 

Dooil KimS I HongDae Sil Lee

Publisher 

MDPI AG

Issue Date 

2006

Citation 

International Journal of Molecular Sciences, vol. 7, no. 11, pp. 519-536

Keywords 

aldose reductasefidarestatfree energymolecular dynamicsstereospecificityaldehyde reductasebinding affinitybinding sitedrug protein bindingstereoisomerism

Abstract 

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 free energy integration techniques. The difference in the free energy of binding was found to be 2.0 ± 1.7 kJ/mol in favour of the (2S,4S)-form, in agreement with the experimental inhibition data. The relative mobilities of the fidarestats complexed with ALR2 indicate a larger entropic penalty for hydrophobic binding of (2R,4S)-fidarestat compared to (2S,4S)-fidarestat, partially explaining its lower binding affinity. The two stereoisomers differ mainly in the orientation of the carbamoyl moiety with respect to the active site and rotation of the bond joining the carbamoyl substituent to the ring. The detailed structural and energetic insights obtained from out simulations allow for a better understanding of the factors determining stereospecific inhibitor-ALR2 binding in the EPF charges model.

ISSN 

1422-0067

Link 

http://dx.doi.org/10.3390/i7110519

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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