title: Kinetics and molecular docking studies of an anti-diabetic complication inhibitor fucosterol from edible brown algae Eisenia bicyclis and Ecklonia stolonifera.
abstract: In the present study, we investigated the anti-diabetic potential of fucosterol by evaluating the ability of this compound to inhibit rat lens aldose reductase (RLAR), human recombinant aldose reductase (HRAR), protein tyrosine phosphatase 1B (PTP1B), and α-glucosidase. Fucosterol displayed moderate inhibitory activity against RLAR, HRAR, and PTP1B. However, it showed weak or no activity against AGE formation and α-glucosidase. In addition, our kinetic study revealed that fucosterol showed a mixed type inhibition against RLAR and HRAR, while it noncompetitively inhibited PTP1B. Since fucosterol inhibited aldose reductase (AR), it holds great promise for use in the treatment of diabetic complications. Therefore, we predicted the 3D structure of AR in rat and human using the Autodock program to simulate binding between AR and fucosterol and evaluate the binding site-directed inhibition of AR by fucosterol. Results of the docking simulations of fucosterol demonstrated negative binding energies (-8.2 kcal/mol for RLAR and -8.5 kcal/mol for HRAR), which indicated a higher affinity and tighter binding capacity of fucosterol for the active site of the enzyme. In particular, the hydrophobic ring system and the aliphatic side chain of fucosterol were found to be tightly bound in a specificity pocket through apolar amino acid residues on AR, while the anion binding site on AR interacts with the 3-hydroxyl group and the double bond on the side chain of fucosterol. The results of the present study clearly demonstrated the potential of using fucosterol for the management and treatment of diabetes and diabetes-associated complications.
authors.affiliation: Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju 561-756, Republic of Korea.
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Jung
authors.forename: Md Nurul
authors.initials: MN
authors.lastname: Islam
authors.forename: Chan Mi
authors.initials: CM
authors.lastname: Lee
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Oh
authors.forename: Sanghyuk
authors.initials: S
authors.lastname: Lee
authors.forename: Jee H
authors.initials: JH
authors.lastname: Jung
authors.forename: Jae Sue
authors.initials: JS
authors.lastname: Choi
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007700:Kinetics; D007908:Lens, Crystalline / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation; D010945:Plants, Edible / Q000737:chemistry*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013265:Stigmasterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000520:alpha-Glucosidases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D011994:Recombinant Proteins; C015896:fucosterol; D013265:Stigmasterol; D000449:Aldehyde Reductase; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D000520:alpha-Glucosidases
keywords: AGE; AR; ARIs; Aldose reductase; Diabetes mellitus; Diabetic complication; Enzyme kinetic; Fucosterol; HRAR; Molecular docking; NADPH; RLAR; advanced glycation endproduct; aldose reductase; aldose reductase inhibitors; human recombinant aldose reductase; rat lens aldose reductase; β-nicotinamide adenine dinucleotide phosphate