Computational analysis of tyrosine phosphatase inhibitor selectivity for the virulence factors YopH and SptP

Hu, Xin; Vujanac, Miloš; Stebbins, C. Erec

doi:10.1016/j.jmgm.2004.05.004

Cited by 15 publications

(11 citation statements)

References 36 publications

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“…Compound (86), only binding to the active site, favored TC-PTP by about twofold. Compound (92), spanning the active and the second phosphotyrosine-binding site, was equally potent against both enzymes. This serves as a good starting point for developing low nanomolar PTP 1B inhibitors by further optimizing the occupancy of the active site and the second phosphotyrosine-binding site.…”

Section: G 2-(oxalylamino)-benzoic Acidmentioning

confidence: 97%

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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: G 2-(oxalylamino)-benzoic Acidmentioning

confidence: 97%

“…YRD motif (Tyr46-Arg47-Asp48) provides features for the phosphatase selectivity. 57,92 5. MECHANISM OF PTP 1B PTP 1B is characterized by presence of a signature motif containing the Cys215 residue that is essential for catalysis.…”

Section: Protein Tyrosine Phosphatase 1b (Ptp 1b)mentioning

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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“…Additional PTPs were also approached using in silico methodologies. Of particular interest was the study by Hu et al, which targeted the identification of small molecule inhibitors for bacterial Yersinia YopH and Salmonella SptP through differentiation with PTP1B [32]. Virtual screening also identified small molecule inhibitors of LMWPTP, SHP-2, and Cdc25 [33], [34], [35].…”

Section: Introductionmentioning

confidence: 99%

Identification of Small Molecule Inhibitors of PTPσ through an Integrative Virtual and Biochemical Approach

Martin

Narang

et al. 2012

PLoS ONE

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PTPσ is a dual-domain receptor type protein tyrosine phosphatase (PTP) with physiologically important functions which render this enzyme an attractive biological target. Specifically, loss of PTPσ has been shown to elicit a number of cellular phenotypes including enhanced nerve regeneration following spinal cord injury (SCI), chemoresistance in cultured cancer cells, and hyperactive autophagy, a process critical to cell survival and the clearance of pathological aggregates in neurodegenerative diseases. Owing to these functions, modulation of PTPσ may provide therapeutic value in a variety of contexts. Furthermore, a small molecule inhibitor would provide utility in discerning the cellular functions and substrates of PTPσ. To develop such molecules, we combined in silico modeling with in vitro phosphatase assays to identify compounds which effectively inhibit the enzymatic activity of PTPσ. Importantly, we observed that PTPσ inhibition was frequently mediated by oxidative species generated by compounds in solution, and we further optimized screening conditions to eliminate this effect. We identified a compound that inhibits PTPσ with an IC50 of 10 µM in a manner that is primarily oxidation-independent. This compound favorably binds the D1 active site of PTPσ in silico, suggesting it functions as a competitive inhibitor. This compound will serve as a scaffold structure for future studies designed to build selectivity for PTPσ over related PTPs.

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“…The most favourable binding poses for both inhibitors involved insertion of their tethered indolyl rings into the previously identified pockets P1 and P2 (Figure 3). [28–30] The higher binding affinity of 3e relative to 3d could be explained by bonding interactions of its indolyl 5-carboxy group with residues in the base of each pocket (the guanidinium group of R473 in Pocket 1 and the amide nitrogen of G442 in the base of pocket 2).…”

Section: Resultsmentioning

confidence: 99%

Oxime‐Based Click Chemistry in the Development of 3‐Isoxazolecarboxylic Acid Containing Inhibitors of Yersinia pestis Protein Tyrosine Phosphatase, YopH

Bahta

Burke

2011

ChemMedChem

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Pathogenicity of Yersinia pestis (Y. pestis) relies on several effector proteins, including YopH, a protein-tyrosine phosphatase. Previously, we screened a library of analogues based on the ubiquitous PTP substrate, p-nitrophenylphosphate (pNPP) and found that incorporation of a 3-phenyl substituent (6-nitro-[1,1'-biphenyl]-3-yl dihydrogen phosphate (1)) enhanced affinity. The current study reports the conversion of 1 from a substrate to inhibitor by replacing the hydrolysable phosphoryl group with a 3-isoxazolecarboxylic acid moiety and by introduction of an aminooxy group and subsequent diversification using oxime-based click chemistry. As reported herein, this approach led to the identification of non-promiscuous low micromolar affinity bidentate YopH inhibitors.

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Computational analysis of tyrosine phosphatase inhibitor selectivity for the virulence factors YopH and SptP

Cited by 15 publications

References 36 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

Identification of Small Molecule Inhibitors of PTPσ through an Integrative Virtual and Biochemical Approach

Oxime‐Based Click Chemistry in the Development of 3‐Isoxazolecarboxylic Acid Containing Inhibitors of Yersinia pestis Protein Tyrosine Phosphatase, YopH

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