Analysis of polyphenolic metabolites from in vitro gastrointestinal digested soft fruit extracts identify malvidin-3-glucoside as an inhibitor of PTP1B

Sisir Kumar Barik, Budheswar Dehury, Wendy R. Russell, Kim-M. Moar, Morven Cruickshank, Lorraine Scobbie, Nigel Hoggard* (Corresponding Author)

*Corresponding author for this work

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Protein-tyrosine phosphatase 1B (PTP1B, EC is an important regulator of insulin signalling. Herein, we employed experimental and computational biology techniques to investigate the inhibitory properties of phenolics, identified from four in vitro gastrointestinal digested (IVGD) soft fruits, on PTP1B. Analysis by LC-MS/MS identified specific phenolics that inhibited PTP1B in vitro. Enzyme kinetics identified the mode of inhibition, while dynamics, stability and binding mechanisms of PTP1B-ligand complex were investigated through molecular modelling, docking, molecular dynamics (MD) simulations, and MM/PBSA binding free energy estimation. IVGD extracts and specific phenolics identified from the four soft fruits inhibited PTP1B (P<0.0001) activity. Among the phenolics tested, the greatest inhibition was shown by malvidin-3-glucoside (P<0.0001) and gallic acid (P<0.0001). Malvidin-3-glucoside (Ki=3.8 µg/mL) was a competitive inhibitor and gallic acid (Ki=33.3 µg/mL) a non-competitive inhibitor of PTP1B. Malvidin-3-glucoside exhibited better binding energy than gallic acid and the synthetic inhibitor Dephostatin (-7.38>-6.37 >-5.62 kcal/mol) respectively. Principal component analysis demonstrated malvidin-3-glucoside PTP1B-complex occupies more conformational space where critical WPD-loop displayed a higher degree of motion. MM/PBSA binding free energy for malvidin-3-glucoside to PTP1B was found to be higher than other complexes mediated by Van der Waals energy rather than electrostatic interaction for the other two inhibitors (-80.32 ± 1.25 > -40.64 ± 1.43 > -21.63±1.73 kcal/mol) respectively. Altogether, we have established novel insights into the specific binding of dietary phenolics and have identified malvidin-3-glucoside as a PTP1B inhibitor, which may be further industrially developed for the treatment of type-2 diabetes.
Original languageEnglish
Article number114109
Number of pages15
JournalBiochemical Pharmacology
Early online date20 Jun 2020
Publication statusPublished - Aug 2020

Bibliographical note


We are grateful to the Scottish Government Rural and Environment Science and Analytical Services (RESAS), the University of Aberdeen and Nutricia Research Foundation for funding. We thank Graham Horgan from Biomathematics and Statistics Scotland for their assistance with the statistical analysis. We thank Gordon J. McDougall and Rex M. Brennan, from The James Hutton Institute for supplying the soft fruits.


  • PTP1B
  • Malvidin-3-glucoside
  • Phenolic
  • Docking
  • Molecular Dynamic Simulation
  • Principal Component Analysis
  • Binding energy
  • Molecular dynamic simulation
  • Principal component analysis


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