Binding modes of peptidomimetics designed to inhibit STAT3.

STAT3 is a transcription factor that has been found to be constitutively activated in a number of human cancers. Dimerization of STAT3 via its SH2 domain and the subsequent translocation of the dimer to the nucleus leads to transcription of anti-apoptotic genes. Prevention of the dimerization is thu...

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Autores principales:	Ankur Dhanik, John S McMurray, Lydia E Kavraki
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/97d7eec2dc1747338a8e4a392dc8b0e6
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spelling	oai:doaj.org-article:97d7eec2dc1747338a8e4a392dc8b0e62021-11-18T08:05:18ZBinding modes of peptidomimetics designed to inhibit STAT3.1932-620310.1371/journal.pone.0051603https://doaj.org/article/97d7eec2dc1747338a8e4a392dc8b0e62012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23251591/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203STAT3 is a transcription factor that has been found to be constitutively activated in a number of human cancers. Dimerization of STAT3 via its SH2 domain and the subsequent translocation of the dimer to the nucleus leads to transcription of anti-apoptotic genes. Prevention of the dimerization is thus an attractive strategy for inhibiting the activity of STAT3. Phosphotyrosine-based peptidomimetic inhibitors, which mimic pTyr-Xaa-Yaa-Gln motif and have strong to weak binding affinities, have been previously investigated. It is well-known that structures of protein-inhibitor complexes are important for understanding the binding interactions and designing stronger inhibitors. Experimental structures of inhibitors bound to the SH2 domain of STAT3 are, however, unavailable. In this paper we describe a computational study that combined molecular docking and molecular dynamics to model structures of 12 peptidomimetic inhibitors bound to the SH2 domain of STAT3. A detailed analysis of the modeled structures was performed to evaluate the characteristics of the binding interactions. We also estimated the binding affinities of the inhibitors by combining MMPB/GBSA-based energies and entropic cost of binding. The estimated affinities correlate strongly with the experimentally obtained affinities. Modeling results show binding modes that are consistent with limited previous modeling studies on binding interactions involving the SH2 domain and phosphotyrosine(pTyr)-based inhibitors. We also discovered a stable novel binding mode that involves deformation of two loops of the SH2 domain that subsequently bury the C-terminal end of one of the stronger inhibitors. The novel binding mode could prove useful for developing more potent inhibitors aimed at preventing dimerization of cancer target protein STAT3.Ankur DhanikJohn S McMurrayLydia E KavrakiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 12, p e51603 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ankur Dhanik John S McMurray Lydia E Kavraki Binding modes of peptidomimetics designed to inhibit STAT3.
description	STAT3 is a transcription factor that has been found to be constitutively activated in a number of human cancers. Dimerization of STAT3 via its SH2 domain and the subsequent translocation of the dimer to the nucleus leads to transcription of anti-apoptotic genes. Prevention of the dimerization is thus an attractive strategy for inhibiting the activity of STAT3. Phosphotyrosine-based peptidomimetic inhibitors, which mimic pTyr-Xaa-Yaa-Gln motif and have strong to weak binding affinities, have been previously investigated. It is well-known that structures of protein-inhibitor complexes are important for understanding the binding interactions and designing stronger inhibitors. Experimental structures of inhibitors bound to the SH2 domain of STAT3 are, however, unavailable. In this paper we describe a computational study that combined molecular docking and molecular dynamics to model structures of 12 peptidomimetic inhibitors bound to the SH2 domain of STAT3. A detailed analysis of the modeled structures was performed to evaluate the characteristics of the binding interactions. We also estimated the binding affinities of the inhibitors by combining MMPB/GBSA-based energies and entropic cost of binding. The estimated affinities correlate strongly with the experimentally obtained affinities. Modeling results show binding modes that are consistent with limited previous modeling studies on binding interactions involving the SH2 domain and phosphotyrosine(pTyr)-based inhibitors. We also discovered a stable novel binding mode that involves deformation of two loops of the SH2 domain that subsequently bury the C-terminal end of one of the stronger inhibitors. The novel binding mode could prove useful for developing more potent inhibitors aimed at preventing dimerization of cancer target protein STAT3.
format	article
author	Ankur Dhanik John S McMurray Lydia E Kavraki
author_facet	Ankur Dhanik John S McMurray Lydia E Kavraki
author_sort	Ankur Dhanik
title	Binding modes of peptidomimetics designed to inhibit STAT3.
title_short	Binding modes of peptidomimetics designed to inhibit STAT3.
title_full	Binding modes of peptidomimetics designed to inhibit STAT3.
title_fullStr	Binding modes of peptidomimetics designed to inhibit STAT3.
title_full_unstemmed	Binding modes of peptidomimetics designed to inhibit STAT3.
title_sort	binding modes of peptidomimetics designed to inhibit stat3.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/97d7eec2dc1747338a8e4a392dc8b0e6
work_keys_str_mv	AT ankurdhanik bindingmodesofpeptidomimeticsdesignedtoinhibitstat3 AT johnsmcmurray bindingmodesofpeptidomimeticsdesignedtoinhibitstat3 AT lydiaekavraki bindingmodesofpeptidomimeticsdesignedtoinhibitstat3
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Binding modes of peptidomimetics designed to inhibit STAT3.

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