Binding of fidarestat stereoisomers with aldose reductase

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.