Rational in silico design of novel α-glucosidase inhibitory peptides and in vitro evaluation of promising candidates

• Published in: Biomedicine & pharmacotherapy 2018-11, Vol.107, p.234-242
• Main Authors: Ibrahim, Mohammed Auwal, Bester, Megan J., Neitz, Albert W., Gaspar, Anabella R.M.
• Format: Article
• Language: English
• Subjects: Acarbose - pharmacology; alpha-Amylases - antagonists & inhibitors; alpha-Amylases - metabolism; alpha-Glucosidases - pharmacology; Animals; Bioactive peptides; Computer Simulation; Diabetes mellitus; Gastrointestinal digestion; Glycoside Hydrolase Inhibitors - pharmacology; In silico analysis; Inhibitory Concentration 50; Kinetics; Molecular docking; Molecular Docking Simulation; Peptides - pharmacology; Sus scrofa; Thermodynamics; α-Glucosidase inhibitors
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2018.07.163

[Display omitted] •4210 peptides were designed and subjected to in silico simulated GIT digestion.•844 GIT resistant peptides were subjected to molecular docking on α-glucosidase.•SVPA and SEPA had the lowest binding free energy against α-glucosidase.•In vitro SVPA and SEPA inhibited both α-glucosidase and α-amylase.•SEPA has potential as a novel α-glucosidase inhibitory peptide for treating diabetes. Treatment of type 2 diabetes is achieved through the inhibition of carbohydrate hydrolyzing enzymes such as α-glucosidase and α-amylase. The present study was conducted to identify novel α-glucosidase inhibitory peptides and to validate the α-glucosidase and α-amylase inhibitory activities of two promising candidates. A total of 4210 potential α-glucosidase inhibitory peptides with 3–5 amino acid residues were designed and individually subjected to in silico simulated gastrointestinal (GIT) digestion using the BIOPEP database. Subsequently, 844 GIT resistant peptides were then subjected to molecular docking using Autodock Vina to determine their binding free energy against human α-glucosidase (PDB ID: 3L4Y). Among all the peptides, SVPA and SEPA were found to have the lowest binding free energies of -8.7 and -8.6 kcal/mol, respectively. Docking of SVPA and SEPA on human α-amylase (PDB ID, 4GQR) identified that both peptides also bind to α-amylase with binding energies of -6.5 and -6.9 kcal/mol, respectively. Hydrogen bond interactions were critical for the binding of both peptides to the α-glucosidase and α-amylase. In vitro, SVPA and SEPA inhibited α-glucosidase and α-amylase activities with IC50 values several fold lower than acarbose except for SVPA that had a significantly higher (p