α-Amylase and dipeptidyl peptidase-4 (DPP-4) inhibitory effects of Melicope latifolia bark extracts and identification of bioactive constituents using in vitro and in silico approaches

Abstract

Context Melicope latifolia (DC.) T. G. Hartley (Rutaceae) was reported to contain various phytochemicals including coumarins, flavonoids, and acetophenones. Objective This study investigates the antidiabetic and antioxidant effects of M. latifolia bark extracts, fractions, and isolated constituents. Materials and methods Melicope latifolia extracts (hexane, chloroform, and methanol), fractions, and isolated constituents with varying concentrations (0.078–10 mg/mL) were subjected to in vitro α-amylase and dipeptidyl peptidase-4 (DPP-4) inhibitory assay. Molecular docking was performed to study the binding mechanism of active compounds towards α-amylase and DPP-4 enzymes. The antioxidant activity of M. latifolia fractions and compounds were determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging and β-carotene bleaching assays. Results Melicope latifolia chloroform extract showed the highest antidiabetic activity (α-amylase IC 50 : 1464.32 μg/mL; DPP-4 IC 50 : 221.58 μg/mL). Fractionation of chloroform extract yielded four major fractions (CF 1 –CF 4 ) whereby CF 3 showed the highest antidiabetic activity (α-amylase IC 50 : 397.68 μg/mL; DPP-4 IC 50 : 37.16 μg/mL) and resulted in β-sitosterol ( 1 ), halfordin ( 2 ), methyl p -coumarate ( 3 ), and protocatechuic acid ( 4 ). Isolation of compounds 2 – 4 from the species and their DPP-4 inhibitory were reported for the first time. Compound 2 showed the highest α-amylase (IC 50 : 197.53 μM) and β-carotene (88.48%) inhibition, and formed the highest number of molecular interactions with critical amino acid residues of α-amylase. The highest DPP-4 inhibition was exhibited by compound 3 (IC 50 : 911.44 μM). Discussion and conclusions The in vitro and in silico analyses indicated the potential of M. latifolia as an alternative source of α-amylase and DPP-4 inhibitors. Further pharmacological studies on the compounds are recommended.

Geraniol ameliorates the progression of high fat‐diet/streptozotocin‐induced type 2 diabetes mellitus in rats via regulation of caspase‐3, Bcl‐2, and Bax expression

“…This suggests that the presence of such interactions could be responsible for the inhibitory activity of geraniol against a‐amylase and α‐glucosidase. Its binding affinity to α‐amylase is close to the acarbose affinity (9.1 kcal/mol) found in the study of Quek et al (2021). A lower or more negative value of the binding affinity indicates a stronger binding contact between the compound and the enzyme.…”

Influence of Gegenqinlian decoction on pharmacokinetics and pharmacodynamics of saxagliptin in type 2 diabetes mellitus rats

“…It was found that the primary target of saxagliptin, dipeptidyl peptidase‐4, is absent in cardiomyocytes, yet saxagliptin internalized into cardiomyocytes and impaired cardiac contractility via inhibition of the Ca 2+ /calmodulin‐dependent protein kinase II‐phospholamban‐sarcoplasmic reticulum Ca 2+ ‐ATPase 2a axis and Na + ‐Ca 2+ exchanger function in Ca 2+ extrusion (Koyani et al., 2017). Moreover, it had been reported that the extract of some herbs could affect the activity of DPP‐4 (Prasannaraja et al., 2020; Quek et al., 2021). Accordingly, whether GQD could affect the activity of DPP‐4 needs further investigation.…”

Natural products from plants targeting key enzymes for the future development of antidiabetic agents

“…Representative DPP-IV inhibitory flavonoids ( 1–72 ) and other aromatic compounds ( 73–100 ) are summarized in Table 1. 42–71 …”