Pyrazoles as novel protein tyrosine phosphatase 1B (PTP1B) inhibitors: An in vitro and in silico study

Rocha, Sónia; Lucas, Mariana; Silva, Vera L. M.; Gomes, Paula; Silva, Artur M. S.; Araújo, Alberto N.; Aniceto, Natália; Guedes, Rita C.; Corvo, M. Luísa; Fernandes, Eduarda; Freitas, Marisa

doi:10.1016/j.ijbiomac.2021.04.061

Cited by 24 publications

(18 citation statements)

References 63 publications

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“…[ 6 ]. PTP-1B is a distinctive enzyme that plays a substantial part in insulin signaling pathways that are implicated in type 2 diabetes and associated metabolic disorders as a negative regulator [ 7 ]. This functions by showing improvement in insulin resistance and normalizing insulin and plasma glucose levels without triggering hypoglycemia.…”

Section: Introductionmentioning

confidence: 99%

Assessment of Antidiabetic Activity of the Shikonin by Allosteric Inhibition of Protein-Tyrosine Phosphatase 1B (PTP1B) Using State of Art: An In Silico and In Vitro Tactics

et al. 2021

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Diabetes mellitus is a multifactorial disease that affects both developing and developed countries and is a major public health concern. Many synthetic drugs are available in the market, which counteracts the associated pathologies. However, due to the propensity of side effects, there is an unmet need for the investigation of safe and effective drugs. This research aims to find a novel phytoconstituent having diminished action on blood glucose levels with the least side effects. Shikonin is a naturally occurring naphthoquinone dying pigment obtained by the roots of the Boraginaceae family. Besides its use as pigments, it can be used as an antimicrobial, anti-inflammatory, and anti-tumor agent. This research aimed to hypothesize the physicochemical and phytochemical properties of Shikonin’s in silico interaction with protein tyrosine phosphate 1B, as well as it’s in vitro studies, in order to determine its potential anti-diabetic impact. To do so, molecular docking experiments with target proteins were conducted to assess their anti-diabetic ability. Analyzing associations with corresponding amino acids revealed the significant molecular interactions between Shikonin and diabetes-related target proteins. In silico pharmacokinetics and toxicity profile of Shikonin using ADMET Descriptor, Toxicity Prediction, and Calculate Molecular Properties tools from Biovia Discovery Studio v4.5. Filter by Lipinski and Veber Rule’s module from Biovia Discovery Studio v4.5 was applied to assess the drug-likeness of Shikonin. The in vitro studies exposed that Shikonin shows an inhibitory potential against the PTP1B with an IC50 value of 15.51 µM. The kinetics studies revealed that it has a competitive inhibitory effect (Ki = 7.5 M) on the enzyme system, which could be useful in the production of preventive and therapeutic agents. The findings of this research suggested that the Shikonin could be used as an anti-diabetic agent and can be used as a novel source for drug delivery.

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Section: Introductionmentioning

confidence: 99%

Assessment of Antidiabetic Activity of the Shikonin by Allosteric Inhibition of Protein-Tyrosine Phosphatase 1B (PTP1B) Using State of Art: An In Silico and In Vitro Tactics

et al. 2021

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“…Following the consideration of results from the in silico evaluation, orientin had the highest negative binding energy value post-MD simulation and was selected for the in vitro analysis. The inhibitory activity of orientin was determined by the hydrolysis of p-NPP to p-nitrophenol (p-NP), using the method of Rocha et al [34] with modifications. Twenty microliters PTP1B (0.2 units/ml) was added to the wells of the 96 well microtiter plate and diluted with a PTP1B reaction buffer containing 50 mM citrate (pH of 6), 0.1 M sodium chloride, 1 mM EDTA, and 1 mM of dithiothreitol (DTT).…”

Section: Methodsmentioning

confidence: 99%

“…This suggests that orientin could either directly bind to the free PTP1B at a site close to its active site or bind to the PTP1B-substrate complex, the consequence of which the overall reaction rate will decrease, and the product will be produced at a slower rate. In contrast, ursolic acid has been reported to be a noncompetitive inhibitor by Rocha et al [34]. Contradictorily, Ha et al [66] reported ursolic acid to exhibit competitive inhibition against PTP1B.…”

Section: In Vitro Evaluationmentioning

confidence: 98%

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

Rampadarath

Balogun

Pillay

et al. 2022

Journal of Diabetes Research

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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.

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“…Protein-tyrosine phosphatise 1B (PTP1B) is a protein involved in the insulin signalling pathway and a negative regulator in metabolic disorders [ 33 ].…”

Section: Molecular Targets Involved In Diabetes Mellitusmentioning

confidence: 99%

Advanced Bioinformatics Tools in the Pharmacokinetic Profiles of Natural and Synthetic Compounds with Anti-Diabetic Activity

et al. 2021

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Diabetes represents a major health problem, involving a severe imbalance of blood sugar levels, which can disturb the nerves, eyes, kidneys, and other organs. Diabes management involves several synthetic drugs focused on improving insulin sensitivity, increasing insulin production, and decreasing blood glucose levels, but with unclear molecular mechanisms and severe side effects. Natural chemicals extracted from several plants such as Gymnema sylvestre, Momordica charantia or Ophiopogon planiscapus Niger have aroused great interest for their anti-diabetes activity, but also their hypolipidemic and anti-obesity activity. Here, we focused on the anti-diabetic activity of a few natural and synthetic compounds, in correlation with their pharmacokinetic/pharmacodynamic profiles, especially with their blood-brain barrier (BBB) permeability. We reviewed studies that used bioinformatics methods such as predicted BBB, molecular docking, molecular dynamics and quantitative structure-activity relationship (QSAR) to elucidate the proper action mechanisms of antidiabetic compounds. Currently, it is evident that BBB damage plays a significant role in diabetes disorders, but the molecular mechanisms are not clear. Here, we presented the efficacy of natural (gymnemic acids, quercetin, resveratrol) and synthetic (TAK-242, propofol, or APX3330) compounds in reducing diabetes symptoms and improving BBB dysfunctions. Bioinformatics tools can be helpful in the quest for chemical compounds with effective anti-diabetic activity that can enhance the druggability of molecular targets and provide a deeper understanding of diabetes mechanisms.

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Pyrazoles as novel protein tyrosine phosphatase 1B (PTP1B) inhibitors: An in vitro and in silico study

Cited by 24 publications

References 63 publications

Assessment of Antidiabetic Activity of the Shikonin by Allosteric Inhibition of Protein-Tyrosine Phosphatase 1B (PTP1B) Using State of Art: An In Silico and In Vitro Tactics

Assessment of Antidiabetic Activity of the Shikonin by Allosteric Inhibition of Protein-Tyrosine Phosphatase 1B (PTP1B) Using State of Art: An In Silico and In Vitro Tactics

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

Advanced Bioinformatics Tools in the Pharmacokinetic Profiles of Natural and Synthetic Compounds with Anti-Diabetic Activity

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