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Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2

Over expressing in PTPN1 (encoding Protein tyrosine phosphatase 1B, PTP1B), a protein tyrosine phosphatase (PTP) that plays an overall positive role in insulin signaling, is linked to the pathogenesis of diabetes and obesity. The relationship between PTP1B and human diseases exhibits PTP1B as the ta...

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Autores principales: Sun, Su-Xia, Li, Xiao-Bo, Liu, Wen-Bo, Ma, Ying, Wang, Run-Ling, Cheng, Xian-Chao, Wang, Shu-Qing, Liu, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Molecular Diversity Preservation International (MDPI) 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709806/
https://www.ncbi.nlm.nih.gov/pubmed/23774838
http://dx.doi.org/10.3390/ijms140612661
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author Sun, Su-Xia
Li, Xiao-Bo
Liu, Wen-Bo
Ma, Ying
Wang, Run-Ling
Cheng, Xian-Chao
Wang, Shu-Qing
Liu, Wei
author_facet Sun, Su-Xia
Li, Xiao-Bo
Liu, Wen-Bo
Ma, Ying
Wang, Run-Ling
Cheng, Xian-Chao
Wang, Shu-Qing
Liu, Wei
author_sort Sun, Su-Xia
collection PubMed
description Over expressing in PTPN1 (encoding Protein tyrosine phosphatase 1B, PTP1B), a protein tyrosine phosphatase (PTP) that plays an overall positive role in insulin signaling, is linked to the pathogenesis of diabetes and obesity. The relationship between PTP1B and human diseases exhibits PTP1B as the target to treat these diseases. In this article, small weight molecules of the imidazolidine series were screened from databases and optimized on silicon as the inhibitors of PTP1B based on the steric conformation and electronic configuration of thiazolidinedione (TZD) compounds. The top three candidates were tested using an in vitro biological assay after synthesis. Finally, we report a novel inhibitor, Compound 13, that specifically inhibits PTP1B over the closely related phosphatase Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) at 80 μM. Its IC(50) values are reported in this paper as well. This compound was further verified by computer analysis for its ability to combine the catalytic domains of PTP1B and SHP-2 by molecular dynamics (MD) simulations.
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spelling pubmed-37098062013-07-12 Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2 Sun, Su-Xia Li, Xiao-Bo Liu, Wen-Bo Ma, Ying Wang, Run-Ling Cheng, Xian-Chao Wang, Shu-Qing Liu, Wei Int J Mol Sci Article Over expressing in PTPN1 (encoding Protein tyrosine phosphatase 1B, PTP1B), a protein tyrosine phosphatase (PTP) that plays an overall positive role in insulin signaling, is linked to the pathogenesis of diabetes and obesity. The relationship between PTP1B and human diseases exhibits PTP1B as the target to treat these diseases. In this article, small weight molecules of the imidazolidine series were screened from databases and optimized on silicon as the inhibitors of PTP1B based on the steric conformation and electronic configuration of thiazolidinedione (TZD) compounds. The top three candidates were tested using an in vitro biological assay after synthesis. Finally, we report a novel inhibitor, Compound 13, that specifically inhibits PTP1B over the closely related phosphatase Src homology 2 (SH2) domain-containing phosphatase 2 (SHP-2) at 80 μM. Its IC(50) values are reported in this paper as well. This compound was further verified by computer analysis for its ability to combine the catalytic domains of PTP1B and SHP-2 by molecular dynamics (MD) simulations. Molecular Diversity Preservation International (MDPI) 2013-06-17 /pmc/articles/PMC3709806/ /pubmed/23774838 http://dx.doi.org/10.3390/ijms140612661 Text en © 2013 by the authors; licensee MDPI, Basel, Switzerland This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Sun, Su-Xia
Li, Xiao-Bo
Liu, Wen-Bo
Ma, Ying
Wang, Run-Ling
Cheng, Xian-Chao
Wang, Shu-Qing
Liu, Wei
Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2
title Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2
title_full Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2
title_fullStr Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2
title_full_unstemmed Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2
title_short Design, Synthesis, Biological Activity and Molecular Dynamics Studies of Specific Protein Tyrosine Phosphatase 1B Inhibitors over SHP-2
title_sort design, synthesis, biological activity and molecular dynamics studies of specific protein tyrosine phosphatase 1b inhibitors over shp-2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709806/
https://www.ncbi.nlm.nih.gov/pubmed/23774838
http://dx.doi.org/10.3390/ijms140612661
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