Molecular dynamics studies on the interactions of PTP1B with inhibitors: from the first phosphate-binding site to the second one

Wang, Jing‐Fang; Gong, Ke; Wei, Dong‐Qing; Li, Yixue; Chou, Kuo‐Chen

doi:10.1093/protein/gzp012

Cited by 85 publications

(47 citation statements)

References 79 publications

(60 reference statements)

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“…The biological function of DNA and proteins and their intense dynamic mechanisms like allosteric transition [7,48], the drug intercalation into DNA [9], the active and inactive state switching [47], and assembly of microtubules [10], can be studied by analyzing their internal motions [8]. The mechanism of protein-ligand interaction can be studied by two different methods i.e.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Potential entry inhibitors of the envelope protein (E2) of Chikungunya virus: in silico structural modeling, docking and molecular dynamic studies

et al. 2017

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Chikungunya fever is an arboviral infection caused by the Chikungunya virus (CHIKV) and is transmitted by Aedes mosquito. The envelope protein (E2) of Chikungunya virus is involved in attachment of virion with the host cell. The present study was conceptualized to determine the structure of E2 protein of CHIKV and to identify the potential viral entry inhibitors. The secondary and tertiary structure of E2 protein was determined using bioinformatics tools. The mutational analysis of the E2 protein suggested that mutations may stabilize or de-stabilize the structure which may affect the structure-function relationship. In silico screening of various compounds from different databases identified two lead molecules i.e. phenothiazine and bafilomycin. Molecular docking and MD simulation studies of the E2 protein and compound complexes was carried out. This analysis revealed that bafilomycin has high docking score and thus high binding affinity with E2 protein suggesting stable protein-ligand interaction. Further, MD simulations suggested that both the compounds were stabilizing E2 protein. Thus, bafilomycin and phenothiazine may be considered as the lead compounds in terms of potential entry inhibitor for CHIKV. Further, these results should be confirmed by comprehensive cell culture, cytotoxic assays and animal experiments. Certain derivatives of phenothiazines can also be explored in future studies for entry inhibitors against CHIKV. The present investigation thus provides insight into protein structural dynamics of the envelope protein of CHIKV. In addition the study also provides information on the dynamics of interaction of E2 protein with entry inhibitors that will contribute towards structure based drug design.

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Section: Molecular Dynamics Simulationsmentioning

confidence: 99%

Potential entry inhibitors of the envelope protein (E2) of Chikungunya virus: in silico structural modeling, docking and molecular dynamic studies

et al. 2017

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“…PTP1B consists of the N-terminal catalytic domain containing two aryl phosphate-binding sites: a high-affinity catalytic site and a low-affinity non-catalytic site [14]. The C-terminal domain of PTP1B is proline-rich, whereas the hydrophobic amino acid residues 400-435 contribute to location of the enzyme at the cytoplasmic face of the endoplasmic reticulum.…”

Section: Discussionmentioning

confidence: 99%

PTP1B Inhibition Causes Rac1 Activation by Enhancing Receptor Tyrosine Kinase Signaling

Tsuchiya

Kanno²,

Nagaya³

et al. 2014

Cell Physiol Biochem

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Background/Aims: The present study investigated the signaling pathway underlying Rac1 activation induced by the linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA). Methods: Activity of protein tyrosine phosphatase 1B (PTP1B) was assayed under cell-free conditions. Western blot was carried out to quantify phosphorylation of insulin receptor substrate-1 (IRS-1) and Akt in PC-12 cells. Rac1 activity was monitored in the föerster resonance energy transfer (FRET) analysis using living and fixed PC-12 cells. Results: DCP-LA markedly suppressed PTP1B activity in a concentration (100 pM-100 µM)-dependent manner. In the DCP-LA binding assay, fluorescein-conjugated DCP-LA produced a single fluorescent signal band at 60 kDa, corresponding to the molecule of PTP1B, and the signal was attenuated or abolished by co-treatment or pretreatment with non-conjugated DCP-LA. DCP-LA significantly enhanced nerve growth factor (NGF)-stimulated phosphorylation of IRS-1 at Tyr1222 and Akt1/2 at Thr308/309 and Ser473/474 in PC-12 cells. In the FRET analysis, DCP-LA significantly enhanced NGF-stimulated Rac1 activation, which is abrogated by the phosphatidylinositol 3 kinase (PI3K) inhibitor wortmannin, the 3-phosphoinositide-dependent protein kinase-1 (PDK1) inhibitor BX912, or the Akt inhibitor MK2206. Conclusion: The results of the present study show that DCP-LA-induced PTP1B inhibition, possibly through its direct binding, causes Rac1 activation by enhancing a pathway along a receptor tyrosine kinase (RTK)/IRS-1/PI3K/Akt/Rac1 axis.

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“…Wang et al have done many studies of molecular modeling on the metabolizing activity enzymes, such as NAD(P)Hdependent d-xylose reductase, P450s, xylose reductase, and they mainly focus on the binding interaction [83][84][85][86][87][88][89][90]. According to the resolved NMR structures [91,92], influenza A viruses can undergo changes, which may result in extremely toxic and drug resistance,.…”

Section: Cheminformatics Used In the Research Of Hces1mentioning

confidence: 99%

Investigation Binding Patterns of Human Carboxylesterase I (hCES I) with Broad Substrates by MD Simulations

Chu

Min²,

Zhang³

et al. 2013

CTMC

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Human carboxylesterase I (hCES 1) plays an important role in the metabolism and activation of prodrugs, such as, the hydrolysis of a variety of drugs of prodrugs featuring an ester, amide or carbamate function. The bindings of the substrates of different lengths and cocaine to hCES1 at two different binding sites, catalytic site and Z-site, were studies through MD simulations. For each case, the correlation analysis has been performed to explore the binding patterns of a broad range of substrates binding to the hCES1.

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Molecular dynamics studies on the interactions of PTP1B with inhibitors: from the first phosphate-binding site to the second one

Cited by 85 publications

References 79 publications

Potential entry inhibitors of the envelope protein (E2) of Chikungunya virus: in silico structural modeling, docking and molecular dynamic studies

Potential entry inhibitors of the envelope protein (E2) of Chikungunya virus: in silico structural modeling, docking and molecular dynamic studies

PTP1B Inhibition Causes Rac1 Activation by Enhancing Receptor Tyrosine Kinase Signaling

Investigation Binding Patterns of Human Carboxylesterase I (hCES I) with Broad Substrates by MD Simulations

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