Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2

Sun, Su-Xia; Li, Xiaobo; Liu, Wenbo; Ma, Ying; Wang, Run‐Ling; Cheng, Xian-Chao; Wang, Shuqing; Liu, Wei

doi:10.3390/ijms140612661

Cited by 8 publications

(6 citation statements)

References 37 publications

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“…Some reagents showed good properties, but compared to the existing antidiabetic agents such as rosiglitazone, metformin, and pioglitazone, oral PTP1B inhibitors are difficult to design [ 34 ]. Long-term administration of nonspecific T-cell protein-tyrosine phosphatase (TC-PTP) inhibitors can be a problem.…”

Section: Discussionmentioning

confidence: 99%

Antiobesity and Antidiabetes Effects of aCudrania tricuspidataHydrophilic Extract Presenting PTP1B Inhibitory Potential

Kim

Lee

Chung

et al. 2016

BioMed Research International

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Diabetes and obesity represent the major health problems and the most age-related metabolic diseases. Protein-tyrosine phosphatase 1B (PTP1B) has emerged as an important regulator of insulin signal transduction and is regarded as a pharmaceutical target for metabolic disorders. To find novel natural materials presenting therapeutic activities against diabetes and obesity, we screened various herb extracts using a chip screening allowing the determination of PTP1B inhibitory effects of the tested compounds using insulin receptor (IR) as the substrate. Cudrania tricuspidata leaves (CTe) had a strong inhibitory effect on PTP1B activity and substantially inhibited fat accumulation in 3T3-L1 cells. CTe was orally administrated to diet-induced obesity (DIO) mice once daily for 3 weeks after which changes in glucose, insulin metabolism, and fat accumulation were examined. Hepatic enzyme markers (aspartate aminotransferase, AST, and alanine aminotransferase, ALT) and total fat mass and triglyceride levels decreased in CTe-treated mice, whereas body weight and total cholesterol concentration slightly decreased. CTe increased the phosphorylation of IRS-1 and Akt in liver tissue. Furthermore, CTe treatment significantly lowered blood glucose levels and improved insulin secretion in DIO mice. Our results strongly suggest that CTe may represent a promising therapeutic substance against diabetes and obesity.

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Section: Discussionmentioning

confidence: 99%

Antiobesity and Antidiabetes Effects of aCudrania tricuspidataHydrophilic Extract Presenting PTP1B Inhibitory Potential

Kim

Lee

Chung

et al. 2016

BioMed Research International

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“…The same procedures and principals from the earlier in silico physico-chemical evaluations of known HDACIs were applied here to evaluate these novel dual inhibitors [ 42 , 51 ]. ADMET module of Discovery Studio 3.1 was used to predict physical properties.…”

Section: Resultsmentioning

confidence: 99%

Structure based design, synthesis and activity studies of small hybrid molecules as HDAC and G9a dual inhibitors

et al. 2017

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Aberrant enzymatic activities or expression profiles of epigenetic regulations are therapeutic targets for cancers. Among these, histone 3 lysine 9 methylation (H3K9Me2) and global de-acetylation on histone proteins are associated with multiple cancer phenotypes including leukemia, prostatic carcinoma, hepatocellular carcinoma and pulmonary carcinoma. Here, we report the discovery of the first small molecule capable of acting as a dual inhibitor targeting both G9a and HDAC. Our structure based design, synthesis, and screening for the dual activity of the small molecules led to the discovery of compound 14 which displays promising inhibition of both G9a and HDAC in low micro-molar range in cell based assays.

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“…Molecular dynamics simulation was carried out to understand the dynamic behavior of protein‐ligand complex. Here, best docked complexes of compound 3e and diazepam with GABA A receptor were used for MD simulation study using Gromacs 5.1.1 . pH 7.0 was used to fix the protonation states to their normal states.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Evaluation of Anticonvulsant Activity of Some Schiff Bases of 7‐Amino‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one

Nilkanth¹,

Ghorai²,

Sathiyanarayanan

et al. 2020

Chemistry & Biodiversity

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A variety of 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one azomethines and 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one benzamide were prepared, characterized and evaluated for the anticonvulsant activity in the rat using picrotoxin‐induced seizure model. The prepared 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one azomethine derivatives emerged potentially anticonvulsant molecular scaffolds exemplified by compounds, 7‐{(E)‐[(4‐nitrophenyl)methylidene]amino}‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, 7‐[(E)‐{[4‐(dimethylamino)phenyl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, 7‐{(E)‐[(4‐bromo‐2,6‐difluorophenyl)methylidene]amino}‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one and 7‐[(E)‐{[3‐(4‐fluorophenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one. All these four compounds have shown substantial decrease in the wet dog shake numbers and grade of convulsions with respect to the standard drug diazepam. The most active compound, 7‐[(E)‐{[4‐(dimethylamino)phenyl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, exhibited 74 % protection against convulsion which was higher than the standard drug diazepam. Furthermore, to identify the binding mode of the interaction amongst the target analogs and binding site of the benzodiazepine receptor, molecular docking study and molecular dynamic simulation were carried out. Additionally, in silico pharmacokinetic and toxicity predictions of target compounds were carried out using AdmetSAR tool. Results of ADMET studies suggest that the pharmacokinetic parameters of all the target compounds were within the acceptable range to become a potential drug candidate as antiepileptic agents.

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Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2

Cited by 8 publications

References 37 publications

Antiobesity and Antidiabetes Effects of aCudrania tricuspidataHydrophilic Extract Presenting PTP1B Inhibitory Potential

Antiobesity and Antidiabetes Effects of aCudrania tricuspidataHydrophilic Extract Presenting PTP1B Inhibitory Potential

Structure based design, synthesis and activity studies of small hybrid molecules as HDAC and G9a dual inhibitors

Synthesis and Evaluation of Anticonvulsant Activity of Some Schiff Bases of 7‐Amino‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one

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