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Identification of STAT1 and STAT3 Specific Inhibitors Using Comparative Virtual Screening and Docking Validation

Signal transducers and activators of transcription (STATs) facilitate action of cytokines, growth factors and pathogens. STAT activation is mediated by a highly conserved SH2 domain, which interacts with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The active dim...

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Autores principales: Szelag, Malgorzata, Czerwoniec, Anna, Wesoly, Joanna, Bluyssen, Hans A. R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339377/
https://www.ncbi.nlm.nih.gov/pubmed/25710482
http://dx.doi.org/10.1371/journal.pone.0116688
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author Szelag, Malgorzata
Czerwoniec, Anna
Wesoly, Joanna
Bluyssen, Hans A. R.
author_facet Szelag, Malgorzata
Czerwoniec, Anna
Wesoly, Joanna
Bluyssen, Hans A. R.
author_sort Szelag, Malgorzata
collection PubMed
description Signal transducers and activators of transcription (STATs) facilitate action of cytokines, growth factors and pathogens. STAT activation is mediated by a highly conserved SH2 domain, which interacts with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The active dimers induce gene transcription in the nucleus by binding to a specific DNA-response element in the promoter of target genes. Abnormal activation of STAT signaling pathways is implicated in many human diseases, like cancer, inflammation and auto-immunity. Searches for STAT-targeting compounds, exploring the phosphotyrosine (pTyr)-SH2 interaction site, yielded many small molecules for STAT3 but sparsely for other STATs. However, many of these inhibitors seem not STAT3-specific, thereby questioning the present modeling and selection strategies of SH2 domain-based STAT inhibitors. We generated new 3D structure models for all human (h)STATs and developed a comparative in silico docking strategy to obtain further insight into STAT-SH2 cross-binding specificity of a selection of previously identified STAT3 inhibitors. Indeed, by primarily targeting the highly conserved pTyr-SH2 binding pocket the majority of these compounds exhibited similar binding affinity and tendency scores for all STATs. By comparative screening of a natural product library we provided initial proof for the possibility to identify STAT1 as well as STAT3-specific inhibitors, introducing the ‘STAT-comparative binding affinity value’ and ‘ligand binding pose variation’ as selection criteria. In silico screening of a multi-million clean leads (CL) compound library for binding of all STATs, likewise identified potential specific inhibitors for STAT1 and STAT3 after docking validation. Based on comparative virtual screening and docking validation, we developed a novel STAT inhibitor screening tool that allows identification of specific STAT1 and STAT3 inhibitory compounds. This could increase our understanding of the functional role of these STATs in different diseases and benefit the clinical need for more drugable STAT inhibitors with high specificity, potency and excellent bioavailability.
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spelling pubmed-43393772015-03-04 Identification of STAT1 and STAT3 Specific Inhibitors Using Comparative Virtual Screening and Docking Validation Szelag, Malgorzata Czerwoniec, Anna Wesoly, Joanna Bluyssen, Hans A. R. PLoS One Research Article Signal transducers and activators of transcription (STATs) facilitate action of cytokines, growth factors and pathogens. STAT activation is mediated by a highly conserved SH2 domain, which interacts with phosphotyrosine motifs for specific STAT-receptor contacts and STAT dimerization. The active dimers induce gene transcription in the nucleus by binding to a specific DNA-response element in the promoter of target genes. Abnormal activation of STAT signaling pathways is implicated in many human diseases, like cancer, inflammation and auto-immunity. Searches for STAT-targeting compounds, exploring the phosphotyrosine (pTyr)-SH2 interaction site, yielded many small molecules for STAT3 but sparsely for other STATs. However, many of these inhibitors seem not STAT3-specific, thereby questioning the present modeling and selection strategies of SH2 domain-based STAT inhibitors. We generated new 3D structure models for all human (h)STATs and developed a comparative in silico docking strategy to obtain further insight into STAT-SH2 cross-binding specificity of a selection of previously identified STAT3 inhibitors. Indeed, by primarily targeting the highly conserved pTyr-SH2 binding pocket the majority of these compounds exhibited similar binding affinity and tendency scores for all STATs. By comparative screening of a natural product library we provided initial proof for the possibility to identify STAT1 as well as STAT3-specific inhibitors, introducing the ‘STAT-comparative binding affinity value’ and ‘ligand binding pose variation’ as selection criteria. In silico screening of a multi-million clean leads (CL) compound library for binding of all STATs, likewise identified potential specific inhibitors for STAT1 and STAT3 after docking validation. Based on comparative virtual screening and docking validation, we developed a novel STAT inhibitor screening tool that allows identification of specific STAT1 and STAT3 inhibitory compounds. This could increase our understanding of the functional role of these STATs in different diseases and benefit the clinical need for more drugable STAT inhibitors with high specificity, potency and excellent bioavailability. Public Library of Science 2015-02-24 /pmc/articles/PMC4339377/ /pubmed/25710482 http://dx.doi.org/10.1371/journal.pone.0116688 Text en © 2015 Szelag et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Szelag, Malgorzata
Czerwoniec, Anna
Wesoly, Joanna
Bluyssen, Hans A. R.
Identification of STAT1 and STAT3 Specific Inhibitors Using Comparative Virtual Screening and Docking Validation
title Identification of STAT1 and STAT3 Specific Inhibitors Using Comparative Virtual Screening and Docking Validation
title_full Identification of STAT1 and STAT3 Specific Inhibitors Using Comparative Virtual Screening and Docking Validation
title_fullStr Identification of STAT1 and STAT3 Specific Inhibitors Using Comparative Virtual Screening and Docking Validation
title_full_unstemmed Identification of STAT1 and STAT3 Specific Inhibitors Using Comparative Virtual Screening and Docking Validation
title_short Identification of STAT1 and STAT3 Specific Inhibitors Using Comparative Virtual Screening and Docking Validation
title_sort identification of stat1 and stat3 specific inhibitors using comparative virtual screening and docking validation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339377/
https://www.ncbi.nlm.nih.gov/pubmed/25710482
http://dx.doi.org/10.1371/journal.pone.0116688
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