X-Ray Structure of PTP1B in Complex with a New PTP1B Inhibitor

Reddy, M. V V V Sekhar; Ghadiyaram, C.; Panigrahi, Sunil K.; Krishnamurthy, Narasimha Rao; Hosahalli, S.; Chandrasekharappa, Arun P.; Manna, Deepankar; Badiger, Sangamesh E.; Dubey, P. K.; Mangamoori, Lakshmi Narasu

doi:10.2174/09298665113209990089

Cited by 15 publications

(8 citation statements)

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“…To sults [18]. This result showed that the docking technique and parameters used in the present study were similar in the PTP1B system.…”

Section: Molecular Dockingsupporting

confidence: 68%

“…The X-ray crystal complex of PTP1B-IN1834146C (Named: Compound 19 in this study) was downloaded from the database of RCSB Protein Data Bank (PDB) (http://www.pdb.org/pdb/home/home.do), and the PDB code was 2VEU [18]. The structure was prepared in the following procedures: 1) removing the co-crystallized ligand of 19 and structural water molecules from the crystal structure, 2) adding hydrogen atoms to the protein by the Biopolymer module implemented in the SYBYL X1.3, and 3) assigning the Kollman-All atom charges to the protein atoms.…”

Section: Data Preparationmentioning

confidence: 99%

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Study on the Interactions of Two Isomer Selaginellins as Novel Small Molecule Inhibitors Targeting PTP1B by Docking and Molecular Dynamics Simulations

Wang¹,

Wang²,

Meng³

et al. 2018

OALib

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Protein Tyrosine Phosphatase 1B (PTP1B) plays a key role in down-regulation of insulin and leptin signaling pathways. Therefore, development of novel inhibitors of PTP1B has becoming research focus in reducing blood sugar levels for Diabetes Mellitus and Obesity. Hence, we selected two isomer Selaginellins (1 and 2) to explain and analyze the binding mechanism of the two potential inhibitors against the PTP1B by molecule docking and molecular dynamics simulations. Firstly, the two isomers (1 and 2) and the initial ligand 19 were docked to the receptor of PTP1B by using molecular docking technology. Secondly, taken the 19 as an indicator, molecular dynamic (MD) simulations and molecular mechanics/generalized born surface area (MM/GBSA) methods were requested to assess the binding affinity and complex stability of the two chemicals towards PTP1B. Finally, we explained that the interactions of compound 1 and 2 take up the active binding site PTP1B. Simultaneously, energy decomposition analysis recognized several amino acid residues situated in substrate-binding site that might provide clues for future inhibitor exploitation towards PTP1B. In conclusion, these results may explain the reasons of differences of optical isomer biological activity and provide valuable information for developing novel inhibitors targeting PTP1B-mediated glucose transport and metabolism for Diabetes Mellitus and Obesity therapeutics.

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“…To sults [18]. This result showed that the docking technique and parameters used in the present study were similar in the PTP1B system.…”

Section: Molecular Dockingsupporting

confidence: 68%

Section: Data Preparationmentioning

confidence: 99%

Study on the Interactions of Two Isomer Selaginellins as Novel Small Molecule Inhibitors Targeting PTP1B by Docking and Molecular Dynamics Simulations

Wang¹,

Wang²,

Meng³

et al. 2018

OALib

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“…The docking result of silydianin was also compared with some of the reported inhibitors (PDB ID: 5T19, 2QBP, 1T49 and 4I8N) and it was observed to be interacting with the residues of the active site. Arg221 and Gln266 were observed to be common interacting residues in silydianin and the reported inhibitors [ 60 , 61 , 62 , 63 ].…”

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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“…PTP1B is also as key player in cancer serving as both tumor promoter and tumor suppressor depending on the cellular context. (Shi et al, 2008;Barr, 2010;Feldhammer et al, 2013;Malla, Kumar, Kumar, 2013;Reddy et al, 2014).…”

Section: Effects Of Derivatives 2a-2o On Cdc25b and Ptp1b In Vitromentioning

confidence: 99%

Biological evaluation of 2,3-dioxoindolin-N-phenylacetamide derivatives as potent CDC25B and PTP1B phosphatase inhibitors

Jin

Chen

Xia

et al. 2020

Braz. J. Pharm. Sci.

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A series of 2,3-dioxoindolin-N-phenylacetamide derivatives was evaluated for inhibitory activity against CDC25B and PTP1B enzymes. Most of the derivatives showed inhibitory activity against CDC25B (IC 50 = 3.2-23.2 µg/mL) and PTP1B (IC 50 = 2.9-21.4 µg/mL). Compound 2h showed the most inhibitory activity in vitro with IC 50 values of 3.2 and 2.9 µg/mL against CDC25B and PTP1B, respectively, compared with the reference drugs Na 3 VO 4 (IC 50 = 2.7 µg/mL) and oleanolic acid (IC 50 = 2.3 µg/mL). The results of selectivity experiments showed that the 2,3-dioxoindolin-N-phenylacetamide derivatives were selective inhibitors against CDC25B and PTP1B. Enzyme kinetic experiments demonstrated that compound 2h was a specific inhibitor with the typical characteristics of a mixed inhibitor. In cytotoxic activity assays compound 2h had potent activity against A549, HeLa, and HCT116 cell lines. In addition, compound 2h showed potent tumor inhibitory activity in a colo205 xenograft model in vivo.

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X-Ray Structure of PTP1B in Complex with a New PTP1B Inhibitor

Cited by 15 publications

References 0 publications

Study on the Interactions of Two Isomer Selaginellins as Novel Small Molecule Inhibitors Targeting PTP1B by Docking and Molecular Dynamics Simulations

Study on the Interactions of Two Isomer Selaginellins as Novel Small Molecule Inhibitors Targeting PTP1B by Docking and Molecular Dynamics Simulations

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

Biological evaluation of 2,3-dioxoindolin-N-phenylacetamide derivatives as potent CDC25B and PTP1B phosphatase inhibitors

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