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

Taufik Muhammad Fakih,Fransiska Kurniawan,Mudasir Mudasir,Muhammad Yusuf,Daryono Hadi Tjahjono

doi:10.3390/molecules26113251

Abstract

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.

Highlights

Porphyrin-based agents can be an alternative choice for cancer therapy because they have selective cytotoxicity against tumor cells [1]
Porphyrins are a family of organic ring molecules including Heme (Iron protoporphyrin IX), the pigment in red blood cells, an essential molecule for living aerobic organisms, plays a major role in gas exchange, mitochondrial energy production, antioxidant defense, signal transduction, and they represent one of the oldest and most widely studied chemical structures in nature and in biomedical applications [2,3,4]
This study provides new information about the interactions of porphyrins with the cancer suppressor REV-ERBβ and the effects of those interactions on the ability of REV-ERBβ to regulate transcription

Summary

Introduction

Porphyrin-based agents can be an alternative choice for cancer therapy because they have selective cytotoxicity against tumor cells [1]. As the prosthetic moiety of all P450s, Heme is responsible for the remarkable and often exquisite, catalytic prowess of these enzymes [7]. The optimal dose of a porphyrin-based agent is lethal to tumor cells while minimizing damage to adjacent normal tissue [8]. Multi-modal porphyrin-based agents have great potential for use in cancer imaging and therapy [9]. Porphyrins have been useful in photodynamic therapy and fluorescence imaging of cancer because of their tumor avidity and favorable photophysical properties, such as long wavelength absorption and emission, easy derivatization, high singlet oxygen quantum yield, and low in vivo toxicity [10,11]. Porphyrins are excellent metal chelators that form highly stable metallocomplexes, making them efficient delivery vehicles for radioisotopes [12]

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Conclusion