In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells.

Octamer-binding transcription factor 4 (Oct4) is a core regulator in the retention of stemness, invasive, and self-renewal properties in glioma initiating cells (GSCs) and its overexpression inhibits the differentiation of glioma cells promoting tumor cell proliferation. The Pit-Oct-Unc (POU) domain...

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Autores principales:	Chirasmita Nayak, Sanjeev Kumar Singh
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ac31aa3c655c4bdfaeba0bf5375cfa22
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spelling	oai:doaj.org-article:ac31aa3c655c4bdfaeba0bf5375cfa222021-12-02T20:17:18ZIn silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells.1932-620310.1371/journal.pone.0255803https://doaj.org/article/ac31aa3c655c4bdfaeba0bf5375cfa222021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0255803https://doaj.org/toc/1932-6203Octamer-binding transcription factor 4 (Oct4) is a core regulator in the retention of stemness, invasive, and self-renewal properties in glioma initiating cells (GSCs) and its overexpression inhibits the differentiation of glioma cells promoting tumor cell proliferation. The Pit-Oct-Unc (POU) domain comprising POU-specific domain (POUS) and POU-type homeodomain (POUHD) subdomains is the most critical part of the Oct4 for the generation of induced pluripotent stem cells from somatic cells that lead to tumor initiation, invasion, posttreatment relapse, and therapeutic resistance. Therefore, the present investigation hunts for natural product inhibitors (NPIs) against the POUHD domain of Oct4 by employing receptor-based virtual screening (RBVS) followed by binding free energy calculation and molecular dynamics simulation (MDS). RBVS provided 13 compounds with acceptable ranges of pharmacokinetic properties and good docking scores having key interactions with the POUHD domain. More Specifically, conformational and interaction stability analysis of 13 compounds through MDS unveiled two compounds ZINC02145000 and ZINC32124203 which stabilized the backbone of protein even in the presence of linker and POUS domain. Additionally, ZINC02145000 and ZINC32124203 exhibited stable and strong interactions with key residues W277, R242, and R234 of the POUHD domain even in dynamic conditions. Interestingly, ZINC02145000 and ZINC32124203 established communication not only with the POUHD domain but also with the POUS domain indicating their incredible potency toward thwarting the function of Oct4. ZINC02145000 and ZINC32124203 also reduced the flexibility and escalated the correlations between the amino acid residues of Oct4 evidenced by PCA and DCCM analysis. Finally, our examination proposed two NPIs that can impede the Oct4 function and may help to improve overall survival, diminish tumor relapse, and achieve a cure not only in deadly disease GBM but also in other cancers with minimal side effects.Chirasmita NayakSanjeev Kumar SinghPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 10, p e0255803 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chirasmita Nayak Sanjeev Kumar Singh In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells.
description	Octamer-binding transcription factor 4 (Oct4) is a core regulator in the retention of stemness, invasive, and self-renewal properties in glioma initiating cells (GSCs) and its overexpression inhibits the differentiation of glioma cells promoting tumor cell proliferation. The Pit-Oct-Unc (POU) domain comprising POU-specific domain (POUS) and POU-type homeodomain (POUHD) subdomains is the most critical part of the Oct4 for the generation of induced pluripotent stem cells from somatic cells that lead to tumor initiation, invasion, posttreatment relapse, and therapeutic resistance. Therefore, the present investigation hunts for natural product inhibitors (NPIs) against the POUHD domain of Oct4 by employing receptor-based virtual screening (RBVS) followed by binding free energy calculation and molecular dynamics simulation (MDS). RBVS provided 13 compounds with acceptable ranges of pharmacokinetic properties and good docking scores having key interactions with the POUHD domain. More Specifically, conformational and interaction stability analysis of 13 compounds through MDS unveiled two compounds ZINC02145000 and ZINC32124203 which stabilized the backbone of protein even in the presence of linker and POUS domain. Additionally, ZINC02145000 and ZINC32124203 exhibited stable and strong interactions with key residues W277, R242, and R234 of the POUHD domain even in dynamic conditions. Interestingly, ZINC02145000 and ZINC32124203 established communication not only with the POUHD domain but also with the POUS domain indicating their incredible potency toward thwarting the function of Oct4. ZINC02145000 and ZINC32124203 also reduced the flexibility and escalated the correlations between the amino acid residues of Oct4 evidenced by PCA and DCCM analysis. Finally, our examination proposed two NPIs that can impede the Oct4 function and may help to improve overall survival, diminish tumor relapse, and achieve a cure not only in deadly disease GBM but also in other cancers with minimal side effects.
format	article
author	Chirasmita Nayak Sanjeev Kumar Singh
author_facet	Chirasmita Nayak Sanjeev Kumar Singh
author_sort	Chirasmita Nayak
title	In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells.
title_short	In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells.
title_full	In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells.
title_fullStr	In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells.
title_full_unstemmed	In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells.
title_sort	in silico identification of natural product inhibitors against octamer-binding transcription factor 4 (oct4) to impede the mechanism of glioma stem cells.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/ac31aa3c655c4bdfaeba0bf5375cfa22
work_keys_str_mv	AT chirasmitanayak insilicoidentificationofnaturalproductinhibitorsagainstoctamerbindingtranscriptionfactor4oct4toimpedethemechanismofgliomastemcells AT sanjeevkumarsingh insilicoidentificationofnaturalproductinhibitorsagainstoctamerbindingtranscriptionfactor4oct4toimpedethemechanismofgliomastemcells
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In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells.

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