Structural Bases for Hesperetin Derivatives: Inhibition of Protein Tyrosine Phosphatase 1B, Kinetics Mechanism and Molecular Docking Study

Md Yousof Ali,Hyun-Ah Jung,Susoma Jannat,Jae-Sue Choi

doi:10.3390/molecules26247433

Abstract

In the present study, we investigated the structure-activity relationship of naturally occurring hesperetin derivatives, as well as the effects of their glycosylation on the inhibition of diabetes-related enzyme systems, protein tyrosine phosphatase 1B (PTP1B) and α-glycosidase. Among the tested hesperetin derivatives, hesperetin 5-O-glucoside, a single-glucose-containing flavanone glycoside, significantly inhibited PTP1B with an IC50 value of 37.14 ± 0.07 µM. Hesperetin, which lacks a sugar molecule, was the weakest inhibitor compared to the reference compound, ursolic acid (IC50 = 9.65 ± 0.01 µM). The most active flavanone hesperetin 5-O-glucoside suggested that the position of a sugar moiety at the C-5-position influences the PTP1B inhibition. It was observed that the ability to inhibit PTP1B is dependent on the nature, position, and number of sugar moieties in the flavonoid structure, as well as conjugation. In the kinetic study of PTP1B enzyme inhibition, hesperetin 5-O-glucoside led to mixed-type inhibition. Molecular docking studies revealed that hesperetin 5-O-glucoside had a higher binding affinity with key amino residues, suggesting that this molecule best fits the PTP1B allosteric site cavity. The data reported here support hesperetin 5-O-glucoside as a hit for the design of more potent and selective inhibitors against PTP1B in the search for a new anti-diabetic treatment.

Highlights

Diabetes mellitus (DM) has emerged as a major threat to human health, and the expected number of diabetic patients will exceed 642 million by 2045 globally [1,2]
Neohesperidin and hesperetin displayed weak protein tyrosine phosphatase 1B (PTP1B) inhibitory activity with corresponding IC50 values of 143.63 ± 3.04 and 288.01 ± 7.98 μM, respectively, while hesperetin 7-O-glucoside was inactive in the PTP1B inhibitory assay
This study demonstrates that, at the allosteric site of PTP1B, there is a prominent interaction of hesperetin 5-Oglucoside with the key residue Asn193 and confirms the mixed-type allosteric inhibition of PTP1B

Summary

Introduction

Diabetes mellitus (DM) has emerged as a major threat to human health, and the expected number of diabetic patients will exceed 642 million by 2045 globally [1,2]. Among the PTP family, PTP1B is a critical member and is in charge of insulin and leptin signaling pathways, and is a negative regulator of the insulin receptor (IR) signal transduction pathway that leads to insulin resistance, which makes this enzyme a promising therapeutic target to manage DM [7,8]. Mice with PTP1B gene knockouts have enhanced insulin sensitivity and low body weight, even when fed a high-fat diet [10]. For these reasons, PTP1B has become an active therapeutic target for the treatment of type II diabetes. PTP1B is an attractive target in the development of new treatments for DM and other related metabolic syndromes

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