To improve current understanding of the role of stilbenoids in the management of diabetes, the hypoglycaemic potential of resveratrol derivatives was investigated in terms of alpha-amylase inhibition. To tackle the mechanistic and structural issues of the interaction with the target protein, bioactive agents were prepared as single molecules, to be used for biological evaluation of the binding determinants. Some dimeric stilbenoids – trans-delta-viniferins, in particular – were found to be much better inhibitors of pancreatic α-amylase.than the reference drug, acarbose. Racemic mixtures of viniferins were more effective than the respective isolated pure enantiomers at equivalent total concentration. A markedly sigmoidal inhibition curve was observed for the (S, S) enantiomer of trans-delta-viniferin, with a Hill cooperativity coefficient (nH) close to 4 and a relatively high Kiapp (0.058 mM). In contrast, values of nH were close to unity for the (R, R) enantiomer (nH = 1.5; Kiapp = 0.043 mM) and for the high-affinity binding of an equimolar mixture of the (R, R) and (S, S) enantiomers (nH = 1.2; Kiapp = 0.012 mM). Molecular docking analysis provided a thermodynamics-based rationale for the inhibitory ability of individual stilbenoids, for the cooperative behavior of viniferin enantiomers, and for the synergistic inhibition discussed above. Indeed, binding of additional ligands on the surface of alpha-amylase was found to decrease the dissociation constant of inhibitors bound to the active site of the enzyme. Finally, viniferins do not appear to compete with acarbose in the inhibition of pancreatic α-amylase. Rather, the evidence gathered so far points to a possible synergy among these classes of inhibitors, in spite of their remarkable structural differences. Studies are in progress to assess whether these synergistic effects could be relevant to developing therapeutic or preventive strategies for diabetes management.
Inhibition of pancreatic α-amilase by resveratrol-derived viniferins relates to their geometrical features and implies co-operative binding
Mauro Marengo;
2019-01-01
Abstract
To improve current understanding of the role of stilbenoids in the management of diabetes, the hypoglycaemic potential of resveratrol derivatives was investigated in terms of alpha-amylase inhibition. To tackle the mechanistic and structural issues of the interaction with the target protein, bioactive agents were prepared as single molecules, to be used for biological evaluation of the binding determinants. Some dimeric stilbenoids – trans-delta-viniferins, in particular – were found to be much better inhibitors of pancreatic α-amylase.than the reference drug, acarbose. Racemic mixtures of viniferins were more effective than the respective isolated pure enantiomers at equivalent total concentration. A markedly sigmoidal inhibition curve was observed for the (S, S) enantiomer of trans-delta-viniferin, with a Hill cooperativity coefficient (nH) close to 4 and a relatively high Kiapp (0.058 mM). In contrast, values of nH were close to unity for the (R, R) enantiomer (nH = 1.5; Kiapp = 0.043 mM) and for the high-affinity binding of an equimolar mixture of the (R, R) and (S, S) enantiomers (nH = 1.2; Kiapp = 0.012 mM). Molecular docking analysis provided a thermodynamics-based rationale for the inhibitory ability of individual stilbenoids, for the cooperative behavior of viniferin enantiomers, and for the synergistic inhibition discussed above. Indeed, binding of additional ligands on the surface of alpha-amylase was found to decrease the dissociation constant of inhibitors bound to the active site of the enzyme. Finally, viniferins do not appear to compete with acarbose in the inhibition of pancreatic α-amylase. Rather, the evidence gathered so far points to a possible synergy among these classes of inhibitors, in spite of their remarkable structural differences. Studies are in progress to assess whether these synergistic effects could be relevant to developing therapeutic or preventive strategies for diabetes management.
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