Identification of Flavonoid C-Glycosides as Promising Antidiabetics Targeting Protein Tyrosine Phosphatase 1B

Abstract

Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of the insulin signaling pathway, has gained attention as a validated druggable target in the management of type 2 diabetes mellitus (T2DM). The lack of clinically approved PTP1B inhibitors has continued to prompt research in plant-derived therapeutics possibly due to their relatively lesser toxicity profiles. Flavonoid C-glycosides are one of the plant-derived metabolites gaining increased relevance as antidiabetic agents, but their possible mechanism of action remains largely unknown. This study investigates the antidiabetic potential of flavonoid C-glycosides against PTP1B in silico and in vitro. Of the seven flavonoid C-glycosides docked against the enzyme, three compounds (apigenin, vitexin, and orientin) had the best affinity for the enzyme with a binding score of –7.3 kcal/mol each, relative to –7.4 kcal/mol for the reference standard, ursolic acid. A further probe (in terms of stability, flexibility, and compactness) of the complexes over a molecular dynamics time study of 100 ns for the three compounds suggested orientin as the most outstanding inhibitor of PTP1B owing to its overall -34.47 kcal/mol binding energy score compared to ursolic acid (-19.24 kcal/mol). This observation was in accordance with the in vitro evaluation result, where orientin had a half maximal inhibitory concentration (IC50) of 0.18 mg/ml relative to 0.13 mg/ml for the reference standard. The kinetics of inhibition of PTP1B by orientin was mixed-type with V max and K m values of 0.004 μM/s and 0.515 μM. Put together, the results suggest orientin as a potential PTP1B inhibitor and could therefore be further explored in the management T2DM as a promising therapeutic agent.

Bioprospection of Selected Plant Secondary Metabolites as Modulators of the Proteolytic Activity of Plasmodium falciparum Plasmepsin V

“…Additionally, it is a tool that studies the possible biological activity impact that may arise from complex instability and conformational alteration of the enzyme because of ligand binding [ 59 ]. Hence, it is germane to study the behaviour of the compounds at the binding pocket of the enzyme to understand the stability, compactness, and flexibility of the (ligand-enzyme) complex [ 60 ]. The RMSD quantifies the thermodynamic conformational stability of a protein-ligand complex during the MDS period; a lower RMSD indicates greater stability [ 57 ].…”

Current Studies on Molecular Mechanisms of Insulin Resistance

“…Tyrosine residues of IR and IRS are dephosphorylated by PTP1B, which is one of the most well-studied tyrosine phosphatases, acting as a crucial negative regulator of the insulin signaling pathways [122]. PTP1B modulation may be valuable as a prospective therapeutic target for the treatment of T2D, and new PTP1B-targeting inhibitors or medications have been developed [123][124][125][126][127][128]. Due to comparatively lower toxicity, plant-derived medicines have become more prominent.…”

“…Due to comparatively lower toxicity, plant-derived medicines have become more prominent. Rampadarath et al suggested flavonoid C glycosides, particularly orientin, as a possible therapeutic agent in the management of T2D [124]. Low-molecular-weight polymannuronic acid phosphate (LPMP), according to studies by Li et al, may be a promising candidate for an antidiabetic medication since it can reduce oxidative stress and improve insulin sensitivity [127].…”

Screening and identification of potential hypoglycemic and hypolipidemic compounds from aqueous extract of Scutellaria baicalensis Georgi root combing affinity ultrafiltration with multiple drug targets and in silico analysis

“…22 Protein tyrosine phosphatase 1B (PTP1B) negatively regulates cell signalling transmitted from leptin and insulin receptors and has been developed as a new target to cure obesity and type 2 diabetes mellitus (T2DM). 23 In addition, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) is a crucial target enzyme for cholesterol synthesis and has been developed as a target for the treatment of hyperlipidemia. 24 On the other hand, some known T2DM and obesity clinical drugs, such as acarbose and orlistat, have been associated with numerous side effects such as myopathy, abdominal pain, skin rash, abdominal distension, oily stool, and hepatotoxicity.…”

“…Additionally, pancreatic lipase plays an important role in diseases related to lipid metabolism, especially obesity 22 . Protein tyrosine phosphatase 1B (PTP1B) negatively regulates cell signalling transmitted from leptin and insulin receptors and has been developed as a new target to cure obesity and type 2 diabetes mellitus (T2DM) 23 . In addition, 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) is a crucial target enzyme for cholesterol synthesis and has been developed as a target for the treatment of hyperlipidemia 24 .…”