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Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ

Nuclear receptor REV-ERBβ is an overexpressed oncoprotein that has been used as a target for cancer treatment. The metal-complex nature of its ligand, iron protoporphyrin IX (Heme), enables the REV-ERBβ to be used for multiple therapeutic modalities as a photonuclease, a photosensitizer, or a fluore...

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Autores principales: Fakih, Taufik Muhammad, Kurniawan, Fransiska, Yusuf, Muhammad, Mudasir, Mudasir, Tjahjono, Daryono Hadi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198987/
https://www.ncbi.nlm.nih.gov/pubmed/34071361
http://dx.doi.org/10.3390/molecules26113251
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author Fakih, Taufik Muhammad
Kurniawan, Fransiska
Yusuf, Muhammad
Mudasir, Mudasir
Tjahjono, Daryono Hadi
author_facet Fakih, Taufik Muhammad
Kurniawan, Fransiska
Yusuf, Muhammad
Mudasir, Mudasir
Tjahjono, Daryono Hadi
author_sort Fakih, Taufik Muhammad
collection PubMed
description Nuclear receptor REV-ERBβ is an overexpressed oncoprotein that has been used as a target for cancer treatment. The metal-complex nature of its ligand, iron protoporphyrin IX (Heme), enables the REV-ERBβ to be used for multiple therapeutic modalities as a photonuclease, a photosensitizer, or a fluorescence imaging agent. The replacement of iron with cobalt as the metal center of protoporphyrin IX changes the ligand from an agonist to an antagonist of REV-ERBβ. The mechanism behind that phenomenon is still unclear, despite the availability of crystal structures of REV-ERBβ in complex with Heme and cobalt protoporphyrin IX (CoPP). This study used molecular dynamic simulations to compare the effects of REV-ERBβ binding to Heme and CoPP, respectively. The initial poses of Heme and CoPP in complex with agonist and antagonist forms of REV-ERBβ were predicted using molecular docking. The binding energies of each ligand were calculated using the MM/PBSA method. The computed binding affinity of Heme to REV-ERBβ was stronger than that of CoPP, in agreement with experimental results. CoPP altered the conformation of the ligand-binding site of REV-ERBβ, disrupting the binding site for nuclear receptor corepressor, which is required for REV-ERBβ to regulate the transcription of downstream target genes. Those results suggest that a subtle change in the metal center of porphyrin can change the behavior of porphyrin in cancer cell signaling. Therefore, modification of porphyrin-based agents for cancer therapy should be conducted carefully to avoid triggering unfavorable effects.
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spelling pubmed-81989872021-06-14 Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ Fakih, Taufik Muhammad Kurniawan, Fransiska Yusuf, Muhammad Mudasir, Mudasir Tjahjono, Daryono Hadi Molecules Article Nuclear receptor REV-ERBβ is an overexpressed oncoprotein that has been used as a target for cancer treatment. The metal-complex nature of its ligand, iron protoporphyrin IX (Heme), enables the REV-ERBβ to be used for multiple therapeutic modalities as a photonuclease, a photosensitizer, or a fluorescence imaging agent. The replacement of iron with cobalt as the metal center of protoporphyrin IX changes the ligand from an agonist to an antagonist of REV-ERBβ. The mechanism behind that phenomenon is still unclear, despite the availability of crystal structures of REV-ERBβ in complex with Heme and cobalt protoporphyrin IX (CoPP). This study used molecular dynamic simulations to compare the effects of REV-ERBβ binding to Heme and CoPP, respectively. The initial poses of Heme and CoPP in complex with agonist and antagonist forms of REV-ERBβ were predicted using molecular docking. The binding energies of each ligand were calculated using the MM/PBSA method. The computed binding affinity of Heme to REV-ERBβ was stronger than that of CoPP, in agreement with experimental results. CoPP altered the conformation of the ligand-binding site of REV-ERBβ, disrupting the binding site for nuclear receptor corepressor, which is required for REV-ERBβ to regulate the transcription of downstream target genes. Those results suggest that a subtle change in the metal center of porphyrin can change the behavior of porphyrin in cancer cell signaling. Therefore, modification of porphyrin-based agents for cancer therapy should be conducted carefully to avoid triggering unfavorable effects. MDPI 2021-05-28 /pmc/articles/PMC8198987/ /pubmed/34071361 http://dx.doi.org/10.3390/molecules26113251 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fakih, Taufik Muhammad
Kurniawan, Fransiska
Yusuf, Muhammad
Mudasir, Mudasir
Tjahjono, Daryono Hadi
Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ
title Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ
title_full Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ
title_fullStr Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ
title_full_unstemmed Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ
title_short Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ
title_sort molecular dynamics of cobalt protoporphyrin antagonism of the cancer suppressor rev-erbβ
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198987/
https://www.ncbi.nlm.nih.gov/pubmed/34071361
http://dx.doi.org/10.3390/molecules26113251
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