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

Fakih, Taufik Muhammad and Kurniawan, Fransiska and Yusuf, Muhammad and Mudasir, Mudasir and Tjahjono, Daryono Hadi (2021) Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ. MOLECULES, 26 (11).

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Abstract

Nuclear receptor REV-ERB beta 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-ERB beta 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-ERB beta. The mechanism behind that phenomenon is still unclear, despite the availability of crystal structures of REV-ERB beta in complex with Heme and cobalt protoporphyrin IX (CoPP). This study used molecular dynamic simulations to compare the effects of REV-ERB beta binding to Heme and CoPP, respectively. The initial poses of Heme and CoPP in complex with agonist and antagonist forms of REV-ERB beta 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-ERB beta was stronger than that of CoPP, in agreement with experimental results. CoPP altered the conformation of the ligand-binding site of REV-ERB beta, disrupting the binding site for nuclear receptor corepressor, which is required for REV-ERB beta 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.

Item Type: Article
Uncontrolled Keywords: breast cancer; REV-ERB beta; porphyrin; nuclear receptor corepressor (NCoR); molecular dynamics (MD) simulation; porphyrin
Subjects: Q Science > QD Chemistry
Divisions: Faculty of Mathematics and Natural Sciences > Chemistry Department
Depositing User: Sri JUNANDI
Date Deposited: 16 Oct 2024 01:55
Last Modified: 16 Oct 2024 01:55
URI: https://ir.lib.ugm.ac.id/id/eprint/9321

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