Potent Protein Tyrosine Phosphatase 1B Research Articles

A novel fluorescent probe with Aggregation-Induced emission characteristics for PTP1B activity sensing and inhibitor screening

Protein tyrosine phosphatase 1B (PTP1B) is an attractive target for the treatment of metabolic diseases such as type 2 diabetes and obesity. In this study, a novel fluorescent probe with aggregation-induced emission (AIE) characteristics was designed and synthesized. Within the fluorescent probe, a tetraphenylethene core is connected to a peptide sequence that can be specifically recognized and hydrolysed by PTP1B. Due to the dephosphorylation of PTP1B, the fluorescent probe exhibited AIE in a turn-on manner, indicating PTP1B activity. This probe was successfully used to detect PTP1B activity in HepG2 cell lysates. Then, a probe-based method was applied to screen for potential PTP1B inhibitors from a natural product library, and three novel PTP1B inhibitors were discovered. These findings indicated that the proposed approach offers a new avenue for discovering potential PTP1B inhibitors.

Role of Alkannin in the Therapeutic Targeting of Protein-Tyrosine Phosphatase 1B and Aldose Reductase in Type 2 Diabetes: An In Silico and In Vitro Evaluation.

Alkannin is a plant-derived naphthoquinone that is isolated from the Boraginaceae family plants. In our previous studies, we found that shikonin, which is the R-enantiomer of alkannin, has potent antidiabetic activity by inhibiting the action of the aldose reductase (AR) enzyme and the protein-tyrosine phosphatase 1B (PTP1B). Therefore, in this study, we aim to explore the antidiabetic effect of alkannin targeting PTP1B and AR by employing in silico and in vitro techniques. For in silico, we used different parameters such as ADMET analysis, molecular docking, MD simulation, Root Mean Square Deviation (RMSD), protein-ligand mapping, and free binding energy calculation. The in vitro evaluation was done by assessing the inhibitory activity and enzyme kinetics of PTP1B and AR inhibition by alkannin. The in silico studies indicate that alkannin possesses favorable pharmacological properties and possesses strong binding affinity for diabetes target proteins. Hydrogen bonds (Val297, Ala299, Leu300, and Ser302) and hydrophobic interactions (Trp20, Val47, Tyr48, Trp79, Trp111, Phe122, Trp219, Val297, Cys298, Ala299, Leu300, and Leu301) are established by the compound, which potentially improves specificity and aids in the stabilization of the protein-ligand complex. The results from in vitro studies show a potent dose-dependent PTP1B inhibitory activity with an IC50 value of 19.47 μM, and toward AR it was estimated at 22.77 μM. Thus, from the results it is concluded that a low IC50 value of alkannin for both PTP1B and AR along with favorable pharmacological properties and optimal intra-molecular interactions indicates its utilization as a potential drug candidate for the management of diabetes and its end complications.

Chalcone-Monoterpene Derivatives from the Buds of Cleistocalyx operculatus and Their Potential as Protein Tyrosine Phosphatase 1B Inhibitors.

Four new compounds, racemic chalcone-monoterpene hybrids (1-3) and a chalcone (9), along with nine known compounds (4-8, 10-13), have been isolated from the buds of Cleistocalyx operculatus. The chemical structures of the isolated compounds were identified through NMR data analysis and confirmed by computational methods, including electronic circular dichroism (ECD) calculations, and further synthetic approaches. Compounds 1-5 were synthesized via a Diels-Alder reaction, a process informed by biomimetic condensation studies that combined chalcones and monoterpenes. These synthetic approaches also yielded various unnatural chalcone-monoterpene derivatives (14-23). The inhibitory effects on protein tyrosine phosphatase 1B (PTP1B) of both naturally isolated and synthetically obtained compounds were evaluated. Compounds 4, 9, 13, and 16b exhibited potent PTP1B inhibitory activity, with IC50 values ranging from 0.9 ± 0.2 to 3.9 ± 0.7 μM. The enantiomers (+)-4 and (-)-16b showed enhanced activity compared to their respective enantiomers. Kinetic studies indicate that all active compounds inhibit PTP1B through mixed mechanisms, and molecular docking simulations agree with the experimental assays on PTP1B. Our results suggest that chalcone-meroterpene adducts from the buds of C.operculatus exhibit potential as antidiabetic agents, partly due to their PTP1B enzyme inhibition.

Identification of Potent Inhibitors Targeting Protein Tyrosine Phosphatase 1B

Identification of Potent Inhibitors Targeting Protein Tyrosine Phosphatase 1B

Protein tyrosine phosphatase 1B (PTP1B) function, structure, and inhibition strategies to develop antidiabetic drugs.

Tyrosine protein phosphatase non-receptor type 1 (PTP1B; also known as protein tyrosine phosphatase 1B) is a member of the protein tyrosine phosphatase (PTP) family and is a soluble enzyme that plays an essential role in different physiological processes, including the regulation of metabolism, specifically in insulin and leptin sensitivity. PTP1B is crucial in the pathogenesis of type 2 diabetes mellitus and obesity. These biological functions have made PTP1B validated as an antidiabetic and anti-obesity, and potentially anticancer, molecular target. Four main approaches aim to inhibit PTP1B: orthosteric, allosteric, bidentate inhibition, and PTPN1 gene silencing. Developing a potent and selective PTP1B inhibitor is still challenging due to the enzyme's ubiquitous expression, subcellular location, and structural properties. This article reviews the main advances in the study of PTP1B since it was first isolated in 1988, as well as recent contextual information related to the PTP family to which this protein belongs. Furthermore, we offer an overview of the role of PTP1B in diabetes and obesity, and the challenges to developing selective, effective, potent, bioavailable, and cell-permeable compounds that can inhibit the enzyme.

Identification of 1,3,4-Thiadiazolyl-Containing Thiazolidine-2,4-dione Derivatives as Novel PTP1B Inhibitors with Antidiabetic Activity.

Forty-one 1,3,4-thiadiazolyl-containing thiazolidine-2,4-dione derivatives (MY1-41) were designed and synthesized as protein tyrosine phosphatase 1B (PTP1B) inhibitors with activity against diabetes mellitus (DM). All synthesized compounds (MY1-41) presented potential PTP1B inhibitory activities, with half-maximal inhibitory concentration (IC50) values ranging from 0.41 ± 0.05 to 4.68 ± 0.61 μM, compared with that of the positive control lithocholic acid (IC50 = 9.62 ± 0.14 μM). The most potent compound, MY17 (IC50 = 0.41 ± 0.05 μM), was a reversible, noncompetitive inhibitor of PTP1B. Circular dichroism spectroscopy and molecular docking were employed to analyze the binding interaction between MY17 and PTP1B. In HepG2 cells, MY17 treatment could alleviate palmitic acid (PA)-induced insulin resistance by upregulating the expression of phosphorylated insulin receptor substrate and protein kinase B. In vivo, oral administration of MY17 could reduce the fasting blood glucose level and improve glucose tolerance and dyslipidemia in mice suffering from DM.

Pyrazole Scaffold: Potential PTP1B Inhibitors for Diabetes Treatment.

The overexpression of the Protein Tyrosine Phosphatase 1B (PTP1B), a key role in the development of insulin resistance, diabetes (T2DM) and obesity, seems to have a substantial impact as a negative regulator of the insulin and leptin signaling pathways. Therefore, inhibiting PTP1B is a prospective therapeutic approach for the treatment of diabetes and obesity. However, the pyrazole scaffold is expected to be of significant pharmaceutical interest due to its broad spectrum of pharmacological actions. This study aims to focus on the significance of pyrazole scaffold in medicinal chemistry, the impact of PTP1B in diabetes and the therapeutic approach of pyrazole scaffold to treat T2DM. A comprehensive analysis of the published literature in several pharmaceutical and medical databases, such as the Web of Science (WoS), PubMed, ResearchGate, ScienceDirect etc., were indeed successfully completed and classified accordingly. Results: As reviewed, the various derivatives of the pyrazole scaffold exhibited prominent PTP1B inhibitory activity. The result showed that derivatives of oxadiazole and dibenzyl amine, chloro substituents, 1, 3-diaryl pyrazole derivatives with rhodanine-3-alkanoic acid groups, naphthalene and also 1, 3, 5-triazine-1H-pyrazole-triazolothiadiazole derivatives, octyl and tetradecyl derivative, indole- and N-phenylpyrazole-glycyrrhetinic acid derivatives with trifluoromethyl group, 2,3-pyrazole ring-substituted-4,4-dimethyl lithocholic acid derivatives with 4- fluoro phenyl substituted and additional benzene ring in the pyrazole scaffold significantly inhibits PTP1B. In silico study observed that pyrazole scaffold interacted with amino acid residues like TYR46, ASP48, PHE182, TYR46, ALA217 and ILE219. Diabetes is a metabolic disorder that elevates the risk of mortality and severe complications. PTP1B is a crucial component in the management of diabetes and obesity. As a result, PTP1B is a promising therapeutic target for the treatment of T2DM and obesity in humans. We concluded that the pyrazole scaffold has prominent inhibitory potential against PTP1B.

Computer-Aided Strategy on 5-(Substituted benzylidene) Thiazolidine-2,4-Diones to Develop New and Potent PTP1B Inhibitors: QSAR Modeling, Molecular Docking, Molecular Dynamics, PASS Predictions, and DFT Investigations.

A set of 5-(substituted benzylidene) thiazolidine-2,4-dione derivatives was explored to study the main structural requirement for the design of protein tyrosine phosphatase 1B (PTP1B) inhibitors. Utilizing multiple linear regression (MLR) analysis, we constructed a robust quantitative structure-activity relationship (QSAR) model to predict inhibitory activity, resulting in a noteworthy correlation coefficient (R2) of 0.942. Rigorous cross-validation using the leave-one-out (LOO) technique and statistical parameter calculations affirmed the model's reliability, with the QSAR analysis revealing 10 distinct structural patterns influencing PTP1B inhibitory activity. Compound 7e(ref) emerged as the optimal scaffold for drug design. Seven new PTP1B inhibitors were designed based on the QSAR model, followed by molecular docking studies to predict interactions and identify structural features. Pharmacokinetics properties were assessed through drug-likeness and ADMET studies. After that density functional theory (DFT) was conducted to assess the stability and reactivity of potential diabetes mellitus drug candidates. The subsequent dynamic simulation phase provided additional insights into stability and interactions dynamics of the top-ranked compound 11c. This comprehensive approach enhances our understanding of potential drug candidates for treating diabetes mellitus.

Potential protein tyrosine phosphatase 1B and α-glucosidase inhibitory flavonoids from Erythrina variegata: Experimental and computational results

Erythrina variegata L., a member of the Fabaceae family, is a valuable medicinal plant with a rich history of traditional medicinal uses. However, its potential as an antidiabetic agent has remained largely unexplored. In this study, three isoflavonoid compounds, namely eryvarin M (1), eryvarin H (2), and neobavaisoflavone (3), were isolated from E. variegata. These compounds displayed significant inhibitory effects on both protein tyrosine phosphatase 1B and α-glucosidase enzymes. The specific attachment position of the prenyl group to the isoflavonoid skeleton plays a pivotal role in determining the variation in their activity. Moreover, the results obtained from docking simulations corroborate the experimental findings, confirming the robust binding affinities of these metabolites toward the target proteins. The docking analysis further highlights that these compounds exhibit highly negative values of binding-free energies against proteins, indicative of their favorable binding affinities. In addition, the formation of hydrogen bonds in the binding region contributes to their binding interactions. These findings significantly enhance our understanding of the therapeutic potential of both E. variegata and its isoflavonoids as potential inhibitors for diabetes and related metabolic disorders, shedding light on their promising role in the field of diabetes research.

An amalgamated molecular dynamic and Gaussian based 3D-QSAR study for the design of 2,4-thiazolidinediones as potential PTP1B inhibitors

Overexpression of protein tyrosine phosphatase 1B (PTP1B) is the major cause of various diseases such as diabetes, obesity, and cancer. PTP1B has been identified as a negative regulator of the insulin signaling cascade, thereby causing diabetes. Numerous anti-diabetic medications based on thiazolidinedione have been successfully developed; however, 2,4-thiazolidinedione (2,4-TZD) scaffolds have been reported as potential PTP1B inhibitors for the manifestation of type 2 diabetes mellitus involving insulin resistance. In the present study, we have employed amalgamated approach involving MD-simulation studies (100 ns) as well as Gaussian field-based 3D-QSAR to develop a pharmacophoric model of 2,4-TZD as potent PTP1B inhibitors. MD simulation studies of the most potent compound in the PTP1B (PDB Id: 2QBS) binding pocket revealed that compound 43 was stable in the binding pocket and demonstrated excellent binding efficacy within the active site pocket. MM/GBSA results revealed that compound 43, bearing C-5 arylidine substitution, strongly bound to the target as compared to rosiglitazone with ΔGMM/GBSA difference of −11.13 kcal/mol. PCA, Rg, RMSF, RMSD, and SASA were analyzed from the complex's trajectories to anticipate the simulation outcome. We have suggested a series of 2,4-TZD as possible PTP1B inhibitors based on the results of MD simulation and 3D-QSAR studies.

A comprehensive review of anti-diabetic activity of vanadium-based complexes via PTP-1B inhibition mechanism

Inorganic salts of the vanadium have been found to mimic insulin in treating diabetic mellitus. In comparison to inorganic vanadium salts, complexes of vanadium with appropriate organic ligands can improve tissue absorption, efficacy, and reduce toxicity of the metal. An organic vanadyl derivative [bis(ethylmaltolato)oxovanadium(IV)] has been reported as a potential diabetes medication and is currently undergoing phase II clinical trials. The mechanism suggests that vanadium complexes inhibit the enzyme protein tyrosine phosphatase-1B(PTP-1B). Pharmacological, Biochemical and genetic evidences strongly suggest that inhibiting the PTP-1B enzyme could treat both diabetes and obesity, making PTP-1B an interesting target for drug development. Studies have also showed that the over expression of PTP-1B is involved in diabetic and obese patients and its inhibition may be an effective strategy in their treatment. Despite the fact that many natural PTP-1B inhibitors demonstrated promising clinical potential, there is no clinically used PTP-1B inhibitor, most likely due to low activity or a lack of selectivity. Search for more potent and selective PTP-1B inhibitors is still going on. As a result, inhibiting protein tyrosine 1B could be a new therapeutic option for patients at risk of type II diabetes mellitus and obesity. Many vanadium compounds are available as of now, as experimental probes for examining the mechanism of altered insulin action. However more studies are needed to establish its clinical use. Hence it has been proposed to prepare and characterize novel vanadium metal complexes with different coordination environments around vanadyl ion and check their anti diabetes activity.

Development and In silico ADMET Analysis of Novel Flavonoids Derivatives as Potent, Non-Competitive and Selective PTP1B Inhibitors

Diabetes mellitus is a serious disease that threatens human health. The most prevalent type of diabetes mellitus is type 2 (T2DM) which is characterized by the lack of insulin secretion and resistance to insulin in target tissues. Protein Tyrosine Phosphatase 1B (PTP1B) plays an important role in the dephosphorylation of phospho-tyrosine residues from the insulin receptor and its substrate. Studies have shown that overexpression of PTP1B protein and its increased activation have been associated with insulin resistance and thus it is a promising therapeutic target for type 2 diabetes. The discovery of selective and effective inhibitors on the active target site present a great challenge due to the site charge and the high degree of conserved active site. Therefore, the identified allosteric site of enzyme PTP1B was chosen to design and evaluate ligands based on effectiveness and selectivity, then filter the compounds based on their ADMET properties in silico to identify the potential inhibitors of the PTP1B enzyme. Among the designed molecules, 14 compounds were obtained with better affinity and selectivity for PTP1B. Some of these compounds showed acceptable pharmacokinetic properties of ADMET and were expected to be non-mutagenic. Thus, they can be considered as promising PTP1B inhibitors.

Anti-Diabetic Activity of Glycyrrhetinic Acid Derivatives FC-114 and FC-122: Scale-Up, In Silico, In Vitro, and In Vivo Studies.

Type 2 diabetes (T2D) is one of the most common diseases and the 8th leading cause of death worldwide. Individuals with T2D are at risk for several health complications that reduce their life expectancy and quality of life. Although several drugs for treating T2D are currently available, many of them have reported side effects ranging from mild to severe. In this work, we present the synthesis in a gram-scale as well as the in silico and in vitro activity of two semisynthetic glycyrrhetinic acid (GA) derivatives (namely FC-114 and FC-122) against Protein Tyrosine Phosphatase 1B (PTP1B) and α-glucosidase enzymes. Furthermore, the in vitro cytotoxicity assay on Human Foreskin fibroblast and the in vivo acute oral toxicity was also conducted. The anti-diabetic activity was determined in streptozotocin-induced diabetic rats after oral administration with FC-114 or FC-122. Results showed that both GA derivatives have potent PTP1B inhibitory activity being FC-122, a dual PTP1B/α-glucosidase inhibitor that could increase insulin sensitivity and reduce intestinal glucose absorption. Molecular docking, molecular dynamics, and enzymatic kinetics studies revealed the inhibition mechanism of FC-122 against α-glucosidase. Both GA derivatives were safe and showed better anti-diabetic activity in vivo than the reference drug acarbose. Moreover, FC-114 improves insulin levels while decreasing LDL and total cholesterol levels without decreasing HDL cholesterol.

Structural diversification of phenylspirodrimane lactams by employing a biosynthetic intermediate

Phenylspirodrimanes are a kind of meroterpenoids with structural diversity and complexity, exhibiting a wide of biological properties, especially for the lactam derivatives consisting a γ-lactam moiety and N-linked side chains. These compounds were derived from multi-step combination of enzymatic and non-enzymatic conversions of intermediates in their biosynthetic pathways. Stachbotrydial (2) with an o-phthalaldehyde unit was supposed as the high-reactivity intermediate of phenylspirodrimane lactams via nonenzymatic reaction with amines. In the present work, an effective and non-enzymatic diversification strategy was developed for the structural diversification of phenylspirodrimane lactams including monomers and dimers from 2 by feeding structurally various mono- and diamines in the fungus Stachybotrys chartarum cultures. In total, 24 phenylspirodrimane lactams (1, 3–25) including 18 new compounds were synthesized. Among them, stachybocin A (1), a bioactive phenylspirodrimane lactam dimer, was produced with the yield of 18.7 mg/g of cell dry weight. The structures of these compounds were elucidated by extensive spectroscopic data, single-crystal X-ray diffraction (Cu Kα), and calculated electronic circular dichroism (ECD) analyses. Bioassay revealed that compounds 1, 17, and 24 displayed significant inhibitory effect on the inactivated state of hNaV 1.2 channels with IC50 values of 0.22, 2.08, and 0.53 µmol/L, respectively. In addition, 1 showed potent protein tyrosine phosphatase 1B (PTP1B) inhibitory, N-methyl-d-aspartate (NMDA) receptor antagonistic, and anti-inflammatory activities.

Ishophloroglucin A, a potent PTP1B inhibitor isolated from brown alga Ishige okamurae inhibits adipogenesis in 3T3-L1 adipocytes

Ishophloroglucin A (IPA) is one of the most abundant and active compounds in Ishige okamurae and is known to be a potential therapeutic candidate for the improvement of metabolic diseases. However, IPA on the inhibitory effects of protein tyrosine phosphatase 1B (PTP1B) and adipogenesis have not been determined. In this study, we investigated the effects of IPA on the inhibition of PTP1B, the effects on adipogenesis, and its mechanisms of action in 3 T3-L1 adipocytes. The IC50 value of IPA against PTP1B was 0.43 μM, which evidenced the higher inhibition activity than that of ursolic acid, a known PTP1B inhibitor. For further insight, we predicted the 3D structure of PTP1B and used a docking algorithm to simulate the binding between PTP1B and IPA. Molecular docking studies revealed a high and stable binding affinity between IPA and PTP1B and indicated that the IPA could interacts with the amino acid residues located in a region to the active site of PTP1B. Further studies showed that IPA concentrations between 6.25 μM and 25 μM dose-dependently attenuated adipogenesis, which was accompanied by a reduction in adipogenesis-related factors, including PPARγ, C/EBPα, SREBP-1c, and FABP4. Our findings suggested that IPA may be a promising natural compound for the treatment of obesity and related diseases.

Polyketides with IDH1 R132h and PTP1B inhibitory activities from the desert-plant-derived fungus Alternaria sp. HM 134.

Five new polyketides named alternafurones A (1) and B (2), alternapyrones M-O (3–5), together with fourteen known ones (6–19), were isolated from the desert-plant-derived fungus Alternaria sp. HM 134. The structures of the new compounds were elucidated from spectroscopic data and ECD spectroscopic analyses. Alternafurones A and B represent polyketides with an unprecedented 6/5/6 skeleton core. Compounds 1, 2 and 4 showed definite inhibitory activities against isocitrate dehydrogenase 1 gene (IDH1 R132h) with IC50 values of 29.38, 19.41 and 14.14 μg/ml, respectively. Seven compounds (6, 7, 9–12, 14) showed potent protein tyrosine phosphatase 1B (PTP1B) inhibitory activity with IC50 values ranging from 0.97 μg/ml to 89.80 μg/ml.

Inhibitors of recombinant protein-tyrosine phosphatase 1B (PTP1B) from Khaya senegalensis: Towards a strategic target for therapeutic intervention in trypanosomiasis

Background: Tyrosine dephosphorylation, catalyzed by protein-tyrosine phosphatase (PTP), prevents trypanosome differentiation to a procyclic form that lacks diverse mechanisms for survival within the mammalian host's bloodstream. Thus, differentiation to a procyclic form in the mammalian host's bloodstream would be potentially lethal to the parasite. This demonstrates that PTP is a critical regulator of trypanosome differentiation, making it a strategic therapeutic target for trypanosomiasis.Purpose: The in vitro inhibitory effect of seven compounds from the active fraction of Khaya senegalensis stem bark (4‑hydroxy-2-butanone, 1,3-butanediol, 2-methylpropyl butanoate, n-tridecanoic acid (CH3-(CH2)11-COOH), n-tetratriacontane, n-hexadecanoic (CH3-(CH2)14-COOH), and 14-pentadecenoic acid (CH2=CH-(CH2)12-COOH)) on the enzymatic activity of recombinant human PTP1B (MBL-SE332–0050) was investigated in this study.Method: The inhibition study was performed according to the standard procedure for analytical experiment and was monitored spectrophotometrically. PTP1B was assayed with 10 mM of p-nitrophenylphosphate. Bioassay-guided fractionation of methanol stem bark extract from K. senegalensis yielded the potent PTP1B inhibitors. Sodium orthovanadate was used as the positive control for inhibition. The kinetic parameters were determined by Lineweaver-Burk plots and calculated using Sigma Plot (SPCC Inc., Chicago, IL, USA)Results: The active fraction that contains the seven compounds inhibited PTP1B dose-dependently with an IC50 of 1.32 µM. Lineweaver-Burk plots revealed that PTP1B was inhibited non-competitively with a Ki of 0.46 ± 0.03 mg/ml, while sodium orthovanadate inhibited the enzyme competitively with an IC50 of 1.02 µM and Ki of 0.26 ± 0.01 mg/ml. Cleavage of the substrate para-Nitrophenylphosphate (pNPP) by PTP1B showed a KM of 4.99 mM and Vmax of 0.053 µmol/min.Conclusion: The mixture of compounds tested is potent PTP1B inhibitors that could serve as scaffolds for new trypanocidal drug candidates that target protein-tyrosine phosphatase activity.

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

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 Vmax and Km 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.

The role of protein tyrosine phosphatase 1B (PTP1B) in the pathogenesis of type 2 diabetes mellitus and its complications.

Insulin resistance, the most important characteristic of the type 2 diabetes mellitus (T2DM), is mostly caused by impairment in the insulin receptor (IR) signal transduction pathway. Protein tyrosine phosphatase 1B (PTP1B), one of the main negative regulators of the IR signaling pathway, is broadly expressed in various cells and tissues. PTP1B decreases the phosphorylation of the IR resulting in insulin resistance in various tissues. The evidence for the physiological role of PTP1B in regulation of metabolic pathways came from whole-body PTP1B-knockout mice. Whole-body and tissue-specific PTP1B-knockout mice showed improvement in adiposity, insulin resistance, and glucose tolerance. In addition, the key role of PTP1B in the pathogenesis of T2DM and its complications was further investigated in mice models of PTP1B deficient/overexpression. In recent years, targeting PTP1B using PTP1B inhibitors is being considered an attractive target to treat T2DM. PTP1B inhibitors improve the sensitivity of the insulin receptor and have the ability to cure insulin resistance-related diseases. We herein summarized the biological functions of PTP1B in different tissues in vivo and in vitro. We also describe the effectiveness of potent PTP1B inhibitors as pharmaceutical agents to treat T2DM.

Dithiocarbamates as potential PTP1B inhibitors for diabetes management

A library of dithiocarbamate analogues were synthesized as inhibitors of Protein Tyrosine Phosphatase 1B (PTP1B) as a potential treatment option for Type 2 Diabetes Mellitus (T2DM). Twenty analogues were synthesized and tested against PTP1B. Additionally, docking studies were conducted to analyse the binding interactions of the dithiocarbamate scaffold with the target enzyme. Subsequently, the binding affinities of the synthesized compounds were also determined. Although, no correlation between IC50 and ΔG was observed, a low of 0.8 μM and −6.8 Kcal/mol, respectively were obtained.