title: Structure Activity Related, Mechanistic, and Modeling Studies of Gallotannins containing a Glucitol-Core andα-Glucosidase.
abstract: Gallotannins containing a glucitol core, which are only produced by members of the maple (Acer) genus, are more potentα-glucosidase inhibitors than the clinical drug, acarbose. While this activity is influenced by the number of substituents on the glucitol core (e.g. more galloyl groups leads to increased activity), the mechanisms of inhibitory action are not known. Herein, we investigated ligand-enzyme interactions and binding mechanisms of a series of 'glucitol-core containing gallotannins (GCGs)' against theα-glucosidase enzyme. The GCGs included ginnalins A, B and C (containing two, one, and one galloyl/s, respectively), maplexin F (containing 3 galloyls) and maplexin J (containing 4 galloyls). All of the GCGs were noncompetitive inhibitors ofα-glucosidase and their interactions with the enzyme were further explored using biophysical and spectroscopic measurements. Thermodynamic parameters (by isothermal titration calorimetry) revealed a 1:1 binding ratio between GCGs andα-glucosidase. The binding regions between the GCGs andα-glucosidase, probed by a fluorescent tag, 1,1'-bis(4-anilino-5-napththalenesulfonic acid, revealed that the GCGs decreased the hydrophobic surface of the enzyme. In addition, circular dichroism analyses showed that the GCGs bind toα-glucosidase and lead to loss of the secondaryα-helix structure of the protein. Also, molecular modeling was used to predict the binding site between the GCGs and theα-glucosidase enzyme. This is the first study to evaluate the mechanisms of inhibitory activities of gallotannins containing a glucitol core onα-glucosidase.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Ma
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle Road at University City, Guangzhou 510006, China; Pre-Incubator for Innovative Drugs & Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Niesen
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Ang
authors.initials: A
authors.lastname: Cai
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Bongsup P
authors.initials: BP
authors.lastname: Cho
authors.affiliation: Pre-Incubator for Innovative Drugs & Medicine, School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Tan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle Road at University City, Guangzhou 510006, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University, 132 East Circle Road at University City, Guangzhou 510006, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Navindra P
authors.initials: NP
authors.lastname: Seeram
keywords: computational modeling; glucitol-core containing gallotannins (GCGs); isothermal titration calorimetry (ITC); maple; α-glucosidase inhibition