title: Kinetic and molecular docking studies of loganin and 7-O-galloyl-D-sedoheptulose from Corni Fructus as therapeutic agents for diabetic complications through inhibition of aldose reductase.
abstract: 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.
authors.affiliation: Department of Food and Life Science, Pukyong National University, Busan, 608-737, Republic of Korea.
authors.forename: Chan Mee
authors.initials: CM
authors.lastname: Lee
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Jung
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Oh
authors.forename: Chan Hum
authors.initials: CH
authors.lastname: Park
authors.forename: Takashi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Takako
authors.initials: T
authors.lastname: Yokozawa
authors.forename: Jae Sue
authors.initials: JS
authors.lastname: Choi
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D001665:Binding Sites; D020134:Catalytic Domain; D029768:Cornus / Q000737:chemistry; D048909:Diabetes Complications / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006539:Heptoses / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D007202:Indicators and Reagents; D039823:Iridoids / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D011994:Recombinant Proteins
chemical_list: C540464:7-O-galloyl-D-sedoheptulose; D004791:Enzyme Inhibitors; D006539:Heptoses; D007202:Indicators and Reagents; D039823:Iridoids; D011994:Recombinant Proteins; D000449:Aldehyde Reductase; C059516:loganin