Binding Interaction of Betulinic Acid to α-Glucosidase and Its Alleviation on Postprandial Hyperglycemia

Abstract

Inhibiting the intestinal α-glucosidase can effectively control postprandial hyperglycemia for type 2 diabetes mellitus (T2DM) treatment. In the present study, we reported the binding interaction of betulinic acid (BA), a pentacyclic triterpene widely distributed in nature, on α-glucosidase and its alleviation on postprandial hyperglycemia. BA was verified to exhibit a strong inhibitory effect against α-glucosidase with an IC50 value of 16.83 ± 1.16 μM. More importantly, it showed a synergistically inhibitory effect with acarbose. The underlying inhibitory mechanism was investigated by kinetics analysis, surface plasmon resonance (SPR) detection, molecular docking, molecular dynamics (MD) simulation and binding free energy calculation. BA showed a non-competitive inhibition on α-glucosidase. SPR revealed that it had a strong and fast affinity to α-glucosidase with an equilibrium dissociation constant (KD) value of 5.529 × 10−5 M and a slow dissociation. Molecular docking and MD simulation revealed that BA bound to the active site of α-glucosidase mainly due to the van der Waals force and hydrogen bond, and then changed the micro-environment and secondary structure of α-glucosidase. Free energy decomposition indicated amino acid residues such as PHE155, PHE175, HIE277, PHE298, GLU302, TRY311 and ASP347 of α-glucosidase at the binding pocket had strong interactions with BA, while LYS153, ARG210, ARG310, ARG354 and ARG437 showed a negative contribution to binding affinity between BA and α-glucosidase. Significantly, oral administration of BA alleviated the postprandial blood glucose fluctuations in mice. This work may provide new insights into the utilization of BA as a functional food and natural medicine for the control of postprandial hyperglycemia.

Luteolin-Rich Extract of Thespesia garckeana F. Hoffm. (Snot Apple) Contains Potential Drug-Like Candidates and Modulates Glycemic and Oxidoinflammatory Aberrations in Experimental Animals

“…Postprandial elevated sugar level is with an increased risk of diabetes-associated secondary complications [ 77 ]. Therefore, the OGTT suggested the potential usefulness of dietl-eth_ T. garckeana in T2DM subjects with insulin resistance prone to elevated postprandial sugar level [ 78 ].…”

“…Therefore, the OGTT suggested the potential usefulness of dietl-eth_T. garckeana in T2DM subjects with insulin resistance prone to elevated postprandial sugar level [78].…”

Grifolamine A, a novel bis-γ-butyrolactone from Grifola frondosa exerted inhibitory effect on α-glucosidase and their binding interaction: Affinity and molecular dynamics simulation

“…SPR assay was analyzed according to our previously reported methods on a GE Biacore T200 system ( Chen et al, 2022 ). Briefly, activated α-glucosidase was immobilized on a CM5 sensor chip using an amine coupling kit.…”

Guidelines for in vitro testing of hypoglycemic components in food‐grade natural products

“…The purpose of preliminary screening is achieved through the inhibition test of glucose‐regulating enzymes (Q. Wang, Li, et al, 2022; L. M. Wang, Zhang, et al, 2022). The mechanism of hypoglycemic components and enzymes is determined through an inhibition kinetics test (Tian et al, 2019), spectrum analysis (Xue et al, 2022), and SPR analysis (S. Chen et al, 2022). Glucose consumption (L. Chen et al, 2020) and insulin secretion (Casanova et al, 2017) are measured by the cell screening model for further screening.…”