Molecular modeling studies of the novel inhibitors of DNA methyltransferases SGI-1027 and CBC12: implications for the mechanism of inhibition of DNMTs.

DNA methylation is an epigenetic modification that regulates gene expression by DNA methyltransferases (DNMTs). Inhibition of DNMTs is a promising approach for cancer therapy. Recently, novel classes of the quinolone-based compound, SGI-1027, and RG108-procainamide conjugates, CBC12, have been ident...

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Autores principales:	Jakyung Yoo, Sun Choi, José L Medina-Franco
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a6e8e191439642b0a8d1c2755c8dc58e
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spelling	oai:doaj.org-article:a6e8e191439642b0a8d1c2755c8dc58e2021-11-18T07:47:50ZMolecular modeling studies of the novel inhibitors of DNA methyltransferases SGI-1027 and CBC12: implications for the mechanism of inhibition of DNMTs.1932-620310.1371/journal.pone.0062152https://doaj.org/article/a6e8e191439642b0a8d1c2755c8dc58e2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23637988/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203DNA methylation is an epigenetic modification that regulates gene expression by DNA methyltransferases (DNMTs). Inhibition of DNMTs is a promising approach for cancer therapy. Recently, novel classes of the quinolone-based compound, SGI-1027, and RG108-procainamide conjugates, CBC12, have been identified as potent DNMT inhibitors. In this work, we report comprehensive studies using induced-fit docking of SGI-1027 and CBC12 with human DNMT1 and DNMT3A. The docking was performed in the C-terminal MTase catalytic domain, which contains the substrate and cofactor binding sites, in the presence and absence of other domains. Induced-fit docking predicts possible binding modes of the ligands through the appropriate structural changes in the receptor. This work suggests a hypothesis of the inhibitory mechanisms of the new inhibitors which is in agreement with the reported autoinhibitory mechanism. The insights obtained in this work can be used to design DNMT inhibitors with novel scaffolds.Jakyung YooSun ChoiJosé L Medina-FrancoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e62152 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jakyung Yoo Sun Choi José L Medina-Franco Molecular modeling studies of the novel inhibitors of DNA methyltransferases SGI-1027 and CBC12: implications for the mechanism of inhibition of DNMTs.
description	DNA methylation is an epigenetic modification that regulates gene expression by DNA methyltransferases (DNMTs). Inhibition of DNMTs is a promising approach for cancer therapy. Recently, novel classes of the quinolone-based compound, SGI-1027, and RG108-procainamide conjugates, CBC12, have been identified as potent DNMT inhibitors. In this work, we report comprehensive studies using induced-fit docking of SGI-1027 and CBC12 with human DNMT1 and DNMT3A. The docking was performed in the C-terminal MTase catalytic domain, which contains the substrate and cofactor binding sites, in the presence and absence of other domains. Induced-fit docking predicts possible binding modes of the ligands through the appropriate structural changes in the receptor. This work suggests a hypothesis of the inhibitory mechanisms of the new inhibitors which is in agreement with the reported autoinhibitory mechanism. The insights obtained in this work can be used to design DNMT inhibitors with novel scaffolds.
format	article
author	Jakyung Yoo Sun Choi José L Medina-Franco
author_facet	Jakyung Yoo Sun Choi José L Medina-Franco
author_sort	Jakyung Yoo
title	Molecular modeling studies of the novel inhibitors of DNA methyltransferases SGI-1027 and CBC12: implications for the mechanism of inhibition of DNMTs.
title_short	Molecular modeling studies of the novel inhibitors of DNA methyltransferases SGI-1027 and CBC12: implications for the mechanism of inhibition of DNMTs.
title_full	Molecular modeling studies of the novel inhibitors of DNA methyltransferases SGI-1027 and CBC12: implications for the mechanism of inhibition of DNMTs.
title_fullStr	Molecular modeling studies of the novel inhibitors of DNA methyltransferases SGI-1027 and CBC12: implications for the mechanism of inhibition of DNMTs.
title_full_unstemmed	Molecular modeling studies of the novel inhibitors of DNA methyltransferases SGI-1027 and CBC12: implications for the mechanism of inhibition of DNMTs.
title_sort	molecular modeling studies of the novel inhibitors of dna methyltransferases sgi-1027 and cbc12: implications for the mechanism of inhibition of dnmts.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/a6e8e191439642b0a8d1c2755c8dc58e
work_keys_str_mv	AT jakyungyoo molecularmodelingstudiesofthenovelinhibitorsofdnamethyltransferasessgi1027andcbc12implicationsforthemechanismofinhibitionofdnmts AT sunchoi molecularmodelingstudiesofthenovelinhibitorsofdnamethyltransferasessgi1027andcbc12implicationsforthemechanismofinhibitionofdnmts AT joselmedinafranco molecularmodelingstudiesofthenovelinhibitorsofdnamethyltransferasessgi1027andcbc12implicationsforthemechanismofinhibitionofdnmts
_version_	1718422930096914432

Molecular modeling studies of the novel inhibitors of DNA methyltransferases SGI-1027 and CBC12: implications for the mechanism of inhibition of DNMTs.

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