Flavonoids as potent allosteric inhibitors of protein tyrosine phosphatase 1B: molecular dynamics simulation and free energy calculation

Zargari, Farshid; Lotfi, Maryam; Shahraki, Omolbanin; Nikfarjam, Zahra; Shahraki, Javad

doi:10.1080/07391102.2017.1409651

Cited by 19 publications

(8 citation statements)

References 52 publications

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“…During previous years, many QSAR studies have been done to aid the analysis and design of novel PTB1B inhibitors [ 41 ]. In silico studies have shown flavonoids to possess PTP1B-inhibitory activity [ 42 ]. In this study, the QSAR models of the flavonoids with PTP1B were generated to analyze the correlations of the structural molecular descriptors with inhibitory activity.…”

Section: Discussionmentioning

confidence: 99%

Potential Therapeutic Target Protein Tyrosine Phosphatase-1B for Modulation of Insulin Resistance with Polyphenols and Its Quantitative Structure–Activity Relationship

et al. 2022

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The increase in the number of cases of type 2 diabetes mellitus (T2DM) and the complications associated with the side effects of chemical/synthetic drugs have raised concerns about the safety of the drugs. Hence, there is an urgent need to explore and identify natural bioactive compounds as alternative drugs. Protein tyrosine phosphatase 1B (PTP1B) functions as a negative regulator and is therefore considered as one of the key protein targets modulating insulin signaling and insulin resistance. This article deals with the screening of a database of polyphenols against PTP1B activity for the identification of a potential inhibitor. The research plan had two clear objectives. Under first objective, we conducted a quantitative structure–activity relationship analysis of flavonoids with PTP1B that revealed the strongest correlation (R2 = 93.25%) between the number of aromatic bonds (naro) and inhibitory concentrations (IC50) of PTP1B. The second objective emphasized the binding potential of the selected polyphenols against the activity of PTP1B using molecular docking, molecular dynamic (MD) simulation and free energy estimation. Among all the polyphenols, silydianin, a flavonolignan, was identified as a lead compound that possesses drug-likeness properties, has a higher negative binding energy of −7.235 kcal/mol and a pKd value of 5.2. The free energy-based binding affinity (ΔG) was estimated to be −7.02 kcal/mol. MD simulation revealed the stability of interacting residues (Gly183, Arg221, Thr263 and Asp265). The results demonstrated that the identified polyphenol, silydianin, could act as a promising natural PTP1B inhibitor that can modulate the insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Potential Therapeutic Target Protein Tyrosine Phosphatase-1B for Modulation of Insulin Resistance with Polyphenols and Its Quantitative Structure–Activity Relationship

et al. 2022

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“…Zargari et al 73 investigated the molecular interactions between α7 helix and a previously proven the most potent flavonoids namely, MOR (Figure 9) (K i = 5.9 μM), MOK (Figure 9) (K i = 3.15 μM), and DPO (Figure 9) (K i = 2.5 μM). [74][75][76] In terms of the molecular docking analysis, the binding energy was found to be correlated with experimental K i values for each allosteric flavonoid inhibitor; DPO bound to PTP1B with the least binding energy (−8.3 kcal/mol) followed by MOK (−6.5 kcal/mol) and MOR (−5.3 kcal/mol).…”

Section: Natural Plant Products As Ptp1b Allosteric Inhibitorsmentioning

confidence: 99%

Recent advances in the development of allosteric protein tyrosine phosphatase inhibitors for drug discovery

Elhassan

Hou

Fang

2021

Medicinal Research Reviews

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Protein tyrosine phosphatases (PTPs) superfamily catalyzes tyrosine de-phosphorylation which affects a myriad of cellular processes. Imbalance in signal pathways mediated by PTPs has been associated with development of many human diseases including cancer, metabolic, and immunological diseases. Several compelling evidence suggest that many members of PTP family are novel therapeutic targets. However, the clinical development of conventional PTP-based active-site inhibitors originally was hampered by the poor selectivity and pharmacokinetic properties. In this regard, PTPs has been widely dismissed as "undruggable." Nonetheless, allosteric modulation has become increasingly an influential and alternative approach that can be exploited for drug development against PTPs. Unlike active-site inhibitors, allosteric inhibitors exhibit a remarkable targetselectivity, drug-likeness, potency, and in vivo activity. Intriguingly, there has been a high interest in novel allosteric PTPs inhibitors within the last years. In this review, we focus on the recent advances of allosteric inhibitors that have been explored in drug discovery and have shown an excellent result in the development of PTPs-based therapeutics. A special emphasis is placed on the structure-activity relationship and molecular

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“…Furthermore, a cutoff of 12 Å for long-range and LINKS algorithms for H-bond constraints were applied ( Hess et al, 1997 ). The equilibration and production run H-bond outlines between the ligand and AChE were calculated using the g H-bond module of Gromacs, as detailed previously ( Zargari et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

Integration of System Biology Tools to Investigate Huperzine A as an Anti-Alzheimer Agent

et al. 2021

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Aim: The present study aimed to investigate huperzine A as an anti-Alzheimer agent based on the principle that a single compound can regulate multiple proteins and associated pathways, using system biology tools.Methodology: The simplified molecular-input line-entry system of huperzine A was retrieved from the PubChem database, and its targets were predicted using SwissTargetPrediction. These targets were matched with the proteins deposited in DisGeNET for Alzheimer disease and enriched in STRING to identify the probably regulated pathways, cellular components, biological processes, and molecular function. Furthermore, huperzine A was docked against acetylcholinesterase using AutoDock Vina, and simulations were performed with the Gromacs package to take into account the dynamics of the system and its effect on the stability and function of the ligands.Results: A total of 100 targets were predicted to be targeted by huperzine A, of which 42 were regulated at a minimum probability of 0.05. Similarly, 101 Kyoto Encyclopedia of Genes and Genomes pathways were triggered, in which neuroactive ligand–receptor interactions scored the least false discovery rate. Also, huperzine A was predicted to modulate 54 cellular components, 120 molecular functions, and 873 biological processes. Furthermore, huperzine A possessed a binding affinity of −8.7 kcal/mol with AChE and interacted within the active site of AChE via H-bonds and hydrophobic interactions.

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Flavonoids as potent allosteric inhibitors of protein tyrosine phosphatase 1B: molecular dynamics simulation and free energy calculation

Cited by 19 publications

References 52 publications

Potential Therapeutic Target Protein Tyrosine Phosphatase-1B for Modulation of Insulin Resistance with Polyphenols and Its Quantitative Structure–Activity Relationship

Potential Therapeutic Target Protein Tyrosine Phosphatase-1B for Modulation of Insulin Resistance with Polyphenols and Its Quantitative Structure–Activity Relationship

Recent advances in the development of allosteric protein tyrosine phosphatase inhibitors for drug discovery

Integration of System Biology Tools to Investigate Huperzine A as an Anti-Alzheimer Agent

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