Introduction: Diabetes mellitus is a heterogenous group of chronic metabolic disorders that results due to deficiency in insulin secretion and signalling. Multiple factors held responsible for onset of diabetes due to defects in glucose metabolism and cellular signalling mechanism. Over the past few years, many plant derived bioactive compounds have been recorded with increased efficacy and fewer side-effects against variety of diseases.
Methods: In the current study, molecular docking and molecular dynamics simulation approaches were employed to evaluate the tetrapeptides devised from AdMc1 protein of Momordica charantia. Due to unavailability of appropriate template for modelling of 3D structure of AdMc1 protein, I-TASSER server was employed for prediction of good quality tertiary structure. Predicted model was refined by GalaxyRefine Web and evaluated by Verify 3D, ERRAT and Ramachandran plot analysis. Next, a ready-to-dock library of fifty tetrapeptides as potent inhibitors was prepared and docked against aldose reductase (AR), protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, α-amylase and glycogen synthase kinase 3-beta as receptor proteins. Molecular dynamics (MD) simulation was performed on Schrodinger's Desmond Module to check stability of the best docking complex.
Results: Top five ligands were selected against each receptor protein based on their binding pattern and docking scores. Among selected ligands (i.e. VEID, TVEV, AYAY, EEIA, ITTV, TTIT, LPSM, RGIE, TTVE and EIAR) followed all parameters in drug scanning and ADMET screening tests. The MD simulations confirmed that the best selected peptide (i.e. VEID) docked with AR and PTP1B was structurally stable.
Conclusion: In the light of overall results of all analyses employed in this study, the selected ligands could be further processed as potential hypoglycaemic drug candidates.
Keywords: ADMET; Lipinski’s rule of five; Momordica charantia; molecular docking; molecular dynamics simulation.