Discovery of new potent human protein tyrosine phosphatase inhibitors via pharmacophore and QSAR analysis followed by in silico screening

Taha, Mutasem O.; Bustanji, Yasser; Al‐Bakri, Amal G.; Yousef, Al-Motassem; Zalloum, Waleed A.; Almasri, Ihab M.; Atallah, Naji

doi:10.1016/j.jmgm.2006.08.008

Cited by 79 publications

(106 citation statements)

References 62 publications

(92 reference statements)

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“…Therefore, h-PTP 1B inhibitors could increase insulin receptor tyrosine phosphorylation, mimic cellular and in vivo actions of insulin, and lower plasma glucose levels. [24][25][26][27] In our study, the significant decrease in blood glucose caused by papaverine can be attributed, at least partially, to its inhibitory action of h-PTP 1B, a hypothesis that is supported by the initial docking studies and in vitro inhibitory assay. We can't exclude other mechanisms by which papaverine potentiates hypoglycemia, however, further future exploration is required to establish this mechanism.…”

Section: Resultssupporting

confidence: 62%

“…[24][25][26][27] The current project commenced by computer-aided docking simulations to probe potential binding interactions within papaverine/h-PTP 1B complex. Subsequently, we validated our theoretical findings in vitro and in vivo.…”

Section: )mentioning

confidence: 99%

“…The assay as described previously 31) and adapted for the plate reader, was used for the nanomolar detection of liberated phosphate by recombinant h-PTP 1B. 13,27,32,33) The assay used the phosphopeptide Asp-AlaAsp-Glu-phosphoTyr-Leu-Ile-Pro-Gln-Gln-Gly as substrate. This phosphorylated peptide corresponds to the 988-998 catalytic domain of epidermal growth factor receptor, and it is one of the most efficient peptide substrates known for h-PTP 1B.…”

Section: Measurement Of H-ptp 1b Inhibitionmentioning

confidence: 99%

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Docking Simulations and in Vitro Assay Unveil Potent Inhibitory Action of Papaverine against Protein Tyrosine Phosphatase 1B

Bustanji

Taha

Almasri

et al. 2009

Biological & Pharmaceutical Bulletin

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Natural products have played an important role in treating and preventing human diseases.1) An analysis of the origin of the drugs that were launched in the last twenty-five years showed that both natural products and semi-synthetic compounds, derived from natural origin, comprised 34% of all new chemical entities, while 18% of them were synthetic mimics of natural compounds.2) Therefore, natural products are considered important sources for new drugs or lead optimization.2,3) The structural diversity of natural products combined with the fact that they were elaborated within living systems render them more "drug-like" than totally synthetic molecules. 4-7)Papaverine (Fig. 1A) is a prominent member of isoquinoline alkaloids isolated from opium poppy (Papaver somniferum L.).8) It exhibits non-selective smooth muscle relaxant effects, which prompted its widespread clinical use in the treatment of vasospasmic diseases.9-11) Papaverine increases the unidirectional K ϩ influx into muscles causing vasodilatation and muscle relaxant effects. The K ϩ flux is associated with increases in glucose uptake which could be one of the causes of hypoglycemia associated with papaverine use. 12)In a recent publication, we revealed a potent inhibitory action for berberine (Fig. 1B), another prominent isoquinoline alkaloid, against the anti-diabetic target human protein tyrosine phosphatase 1B (h-PTP 1B).13) The chemical similarity between berberine and papaverine combined with the fact that they share common biosynthetic origin, 14,15) prompted us to evaluate any possible inhibitory action of papaverine against h-PTP 1B. Furthermore, several reports have indicated that opiates, including papaverine, possess significant hypoglycemic properties. 16,17) The hypoglycemic mechanism of opiates is still uncertain. Furthermore, the hypoglycemic effect of papaverine is not well characterized using in vivo animal models.h-PTP 1B, a cytosolic non-receptor protein tyrosine phosphatase, has been implicated in the progression of diabetes because it acts as negative regulator of insulin signal transduction. h-PTP 1B directly catalyzes the dephosphorylation of cellular substrates of the insulin receptor kinase resulting in a down-regulation of insulin action. [18][19][20][21] Mice lacking functional h-PTP 1B showed enhanced tyrosine kinase activity and increased sensitivity to insulin. 22) In another animalbased approach, treatment with anti-sense oligonucleotide specific for h-PTP 1B resulted in normalization of blood glucose and insulin levels in animal models of type 2 diabetes. 23)Accordingly, h-PTP 1B inhibitors could increase insulin receptor tyrosine phosphorylation, mimic cellular and in vivo actions of insulin, and lower plasma glucose levels in diabetic animal models. [24][25][26][27] The current project commenced by computer-aided docking simulations to probe potential binding interactions within papaverine/h-PTP 1B complex. Subsequently, we validated our theoretical findings in vitro and in vivo. The structural similarity between papa...

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Section: Resultssupporting

confidence: 62%

Section: )mentioning

confidence: 99%

Section: Measurement Of H-ptp 1b Inhibitionmentioning

confidence: 99%

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Docking Simulations and in Vitro Assay Unveil Potent Inhibitory Action of Papaverine against Protein Tyrosine Phosphatase 1B

Bustanji

Taha

Almasri

et al. 2009

Biological & Pharmaceutical Bulletin

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“…The major benefit of CADD in drug discovery is that it costs much less than any biomedical test of inhibition in cells just like in the references from APS [22][23][24][25][26][27][28] . The ligand based method is built on regression analysis for molecular structure and properties against activities, while the protein based method focuses on the docking procedure in which the structure of the protein would be docked with many kinds of inhibitors and the binding energies would be calculated [29,30] . When the patterns of results in the two methods agree with each other, it indicates a reliable outcome.…”

Section: Introductionmentioning

confidence: 99%

Discovery of potent inhibitors for phosphodiesterase 5 by virtual screening and pharmacophore analysis

et al. 2009

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Aim: To explore the potent inhibitor from one of the Traditional Chinese medicine (TCM), Epimedium sagittatum. Methods: We predicted the potent compound, eS03b, de novo evolution from the four Epimedium sagittatum components were verified by molecular docking, pharmacophore analysis, and analysis of quantitative structure-activity relationship (QSAR) model, which was constructed by multiple linear regression. Results: ES03b was chosen to undergo drug modification via de novo evolution. By analyzing the pharmacophore features, we found that the hydrophobic core in the binding site and the hydrogen bond generated at Asn663 played key roles in designing PDE5 inhibitors. eS03b generated 49 diversities (evo01-49). evo48 had high activity in prediction. Although the value of prediction was overestimated, evo48 was suggested as the potent lead. Conclusion: In this study, we showed that the hydrophobic core in the binding site and hydrogen bond production on Asn663 played key roles to design PDE5 inhibitors. From several require validation analysis, Evo48 was suggested to be a potent inhibitor.

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“…We previously reported the successful use of this combination to probe the induced fit flexibilities of activated factor X 53 and towards the discovery of new inhibitory leads against glycogen synthase kinase-3β, 54 bacterial MurF, 55 protein tyrosine phosphatase, 56 DPP IV, 57 hormone sensitive lipase, 58 β-secretase, 59 influenza neuraminidase, 60 cholesteryl ester transfer protein, 61 cycline dependent kinase, 62 Heat shock protein, 63 estrogen receptor β, 64 β-D-Glucosidase, 65 and β-D-Galactosidase. 66 The author intends in this chapter to discuss the basic theoretical principles of this successful ligand-based approach and to provide interested audiences with experimental details related to this approach.…”

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confidence: 99%

Mixing Pharmacophore Modeling and Classical QSAR Analysis as Powerful Tool for Lead Discovery

Taha¹

2012

Virtual Screening

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Discovery of new potent human protein tyrosine phosphatase inhibitors via pharmacophore and QSAR analysis followed by in silico screening

Cited by 79 publications

References 62 publications

Docking Simulations and in Vitro Assay Unveil Potent Inhibitory Action of Papaverine against Protein Tyrosine Phosphatase 1B

Docking Simulations and in Vitro Assay Unveil Potent Inhibitory Action of Papaverine against Protein Tyrosine Phosphatase 1B

Discovery of potent inhibitors for phosphodiesterase 5 by virtual screening and pharmacophore analysis

Mixing Pharmacophore Modeling and Classical QSAR Analysis as Powerful Tool for Lead Discovery

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