Aldose reductase (AR) is a key
enzyme in the
polyol pathway that is strongly implicated in the pathogenesis of
diabetic complications. AR inhibitors have been proposed as therapeutic agents for
diabetic complications through suppression of
sorbitol formation and accumulation. In this study, we evaluated whether two major compounds of Corni Fructus,
loganin and
7-O-galloyl-D-sedoheptulose, had an inhibitory effect on
diabetic complications through AR inhibition. Because the
iridoid glycoside loganin and the low-molecular-weight
polyphenol 7-O-galloyl-D-sedoheptulose showed marginal inhibitory activities against rat lens AR (RLAR) and human recombinant AR (HRAR) in inhibition assays, we performed
enzyme kinetic analyses and molecular simulation of the interaction of these two compounds with AR to further investigate their potential as inhibitors of
diabetic complications. In kinetic analysis using Lineweaver-Burk plots and Dixon plots,
loganin and
7-O-galloyl-D-sedoheptulose were both mixed inhibitors of RLAR with inhibition constants (K i) of 27.99 and 128.68 μΜ, respectively. Moreover, molecular docking simulation of both compounds demonstrated negative binding energies (Autodock 4.0 = -6.7; -7.5 kcal/mol; Fred 2.0 = -59.4; -63.2 kcal/mol) indicating a high affinity and tight binding capacity for the active site of the
enzyme.
Iridoid nucleus and aromatic ring systems and
glycoside and
sedoheptulose moieties were found to bind tightly to the specificity pocket and the
anion binding pocket in RLAR through Phe123, His111, Trp21, Tyr49, His111, and Trp112 residues. Our results clearly indicate that
loganin and
7-O-galloyl-D-sedoheptulose have great promise for the treatment of
diabetic complications through inhibition of AR.