Formylchromone derivatives as irreversible and selective inhibitors of human protein tyrosine phosphatase 1B. Kinetic and modeling studies

Shim, Yi Sup; Kim, Chul; Lee, Kyung A.; Shrestha, Suja; Lee, Keun‐Hyeung; Kim, Chan Kyung; Cho, Hyeongjin

doi:10.1016/j.bmc.2004.11.006

Cited by 32 publications

(12 citation statements)

References 30 publications

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“…Kinetic studies revealed that formylchromones derivatives are irreversible and active site-directed inhibitors likely by forming covalent adduct with the active site Arg221. 149 Molecular modeling study identified the orientation of the inhibitor bound at the active site of PTP 1B. Compound (99) extended deep into the active site pocket, making several hydrogen bonds and hydrophobic interactions with key residues of the catalytic site.…”

Section: Formylchromonesmentioning

confidence: 99%

Protein Tyrosine Phosphatase 1B Inhibitors: A Molecular Level Legitimate Approach for the Management of Diabetes Mellitus

Thareja

Aggarwal

Bhardwaj

et al. 2010

Medicinal Research Reviews

111

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Diabetes mellitus is a systemic disease responsible for morbidity in the western world and is gradually becoming prevalent in developing countries too. The prevalence of diabetes is rapidly increasing in industrialized countries and type 2 diabetes accounts for 90% of the disease. Insulin resistance is a major pathophysiological factor in the development of type 2 diabetes, occurring mainly in muscle, adipose tissues, and liver leading to reduced glucose uptake and utilization and increased glucose production. The prevalence and rising incidence of diabetes emphasized the need to explore new molecular targets and strategies to develop novel antihyperglycemic agents. Protein Tyrosine Phosphatase 1B (PTP 1B) has recently emerged as a promising molecular level legitimate therapeutic target in the effective management of type 2 diabetes. PTP 1B, a cytosolic nonreceptor PTPase, has been implicated as a negative regulator of insulin signal transduction. Therefore, PTP 1B inhibitors would increase insulin sensitivity by blocking the PTP 1B-mediated negative insulin signaling pathway and might be an attractive target for type 2 diabetes mellitus and obesity. With X-ray crystallography and NMR-based fragment screening, the binding interactions of several classes of inhibitors have been elucidated, which could help the design of future PTP 1B inhibitors. The drug discovery research in PTP 1B is a challenging area to work with and many pharmaceutical organizations and academic research laboratories are focusing their research toward the development of potential PTP 1B inhibitors which would prove to be a milestone for the management of diabetes.

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Section: Formylchromonesmentioning

confidence: 99%

Protein Tyrosine Phosphatase 1B Inhibitors: A Molecular Level Legitimate Approach for the Management of Diabetes Mellitus

Thareja

Aggarwal

Bhardwaj

et al. 2010

Medicinal Research Reviews

111

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“…As shown in Figure 6B, the vehicle-treated reaction exhibited a simple linear progress curve, but in the presence of dysidine, the curves displayed a quasi-linear relationship with time in the early part, converting later to a slower linear relationship. These reaction curves are typical progress curves for slow-binding inhibitors, suggesting that dysidine inhibited PTP1B in a slow-binding manner [37][38][39][40] . By considering the possibility that a slowbinding inhibitor might inhibit enzyme in an irreversible manner, the character of the reversibility or irreversibility of inhibition of PTP1B by dysidine was also inspected.…”

Section: Resultsmentioning

confidence: 81%

A sesquiterpene quinone, dysidine, from the sponge Dysidea villosa, activates the insulin pathway through inhibition of PTPases

Zhang

Guo

et al. 2009

Acta Pharmacol Sin

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Aim:The sesquiterpene hydroquinones/quinones belong to one class of marine sponge metabolites, and they have received considerable attention due to their varied biological activities, including anti-tumor, anti-HIV, and anti-inflammatory action. In order to probe the potential anti-diabetic effect of the sesquiterpene hydroquinones/quinones, the effect of dysidine on the insulin pathway was studied. Methods: The promotion of glucose uptake by dysidine was studied in differentiated 3T3-L1 cells. The increase in membrane-located GLUT4 by dysidine was studied in CHO-K1/GLUT4 and 3T3-L1 cells by immuno-staining. The activation of the insulin signaling pathway by dysidine was probed by Western blotting. The inhibition of PTPases by dysidine was detected in vitro. Results: Dysidine, found in the Hainan sponge Dysidea villosa in the Chinese South Sea, effectively activated the insulin signaling pathway, greatly promoted glucose uptake in 3T3-L1 cells, and showed strong insulin-sensitizing activities. The potential targets of action for dysidine were probed, and the results indicated that dysidine exhibited its cellular effects through activation of the insulin pathway, possibly through the inhibition of protein tyrosine phosphatases, with more specific inhibition against protein tyrosine phosphatase 1B (PTP1B). Conclusion: Our findings are expected to expand understanding of the biological activities of sesquiterpene hydroquinones/quinones, and they show that dysidine could be a potential lead compound in the development of an alternative adjuvant in insulin therapy.

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“…where k app is the apparent first-order inhibition rate constant, K I represents the dissociation constant for the first step of complex (EI complex) formation, k inact is the rate constant for the second step of complex (irreversible EI complex) formation and [I] is the inhibitor concentration [31]. The K I and k inact values of the inhibition of XOD by CYN were determined as 3.05 μM and 0.020 min −1 , respectively ( Figure 5).…”

Section: Resultsmentioning

confidence: 99%

Inhibition of xanthine oxidase by Caulerpenyne from Caulerpa prolifera

Cengiz¹,

Çavaş²,

Yurdakoç³

et al. 2012

Turk J Bioch

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Formylchromone derivatives as irreversible and selective inhibitors of human protein tyrosine phosphatase 1B. Kinetic and modeling studies

Cited by 32 publications

References 30 publications

Protein Tyrosine Phosphatase 1B Inhibitors: A Molecular Level Legitimate Approach for the Management of Diabetes Mellitus

Protein Tyrosine Phosphatase 1B Inhibitors: A Molecular Level Legitimate Approach for the Management of Diabetes Mellitus

A sesquiterpene quinone, dysidine, from the sponge Dysidea villosa, activates the insulin pathway through inhibition of PTPases

Inhibition of xanthine oxidase by Caulerpenyne from Caulerpa prolifera

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