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Author Spotlight: MAPP Protocol – Advancing Glycan Analysis
Published on: September 29, 2023
Identification of potential anti-mucor agents by targeting endothelial cell receptor glucose-regulated protein-78
Anamika Singh1, Ashwin Varadarajan2, Pradeep Pant3
1Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India.
Abstract:
Mucormycosis is a fungal infection of the sinuses, brain and lungs that is the cause of approximately 50% mortality rate despite the available first-line therapy. Glucose-Regulated Protein 78 (GRP78) is already reported to be a novel host receptor that mediates invasion and damage of human endothelial cells by Rhizopus oryzae and Rhizopus delemar, the most common etiologic species of Mucorales. The expression of GRP78 is also regulated by the levels of iron and glucose in the blood. There are several antifungal drugs in the market but they pose a serious side effect to the vital organs of the body. Therefore, there is an immediate need to discover effective drug molecules having increased efficacy with no side effects. With the help of various computational tools, the current study was attempted to determine potential antimucor agents against GRP78. The receptor molecule GRP78 was screened against 8820 known drugs deposited in DrugBank library using high-throughput virtual screening method. Total top 10 compounds were selected based on the binding energies greater than the reference co-crystal molecule. Furthermore, molecular dynamic (MD) simulations using AMBER were performed to calculate the stability of the top-ranked compounds in the active site of GRP78. After extensive computational studies, we propose that two compounds (CID439153 and CID5289104) have inhibitory potency against mucormycosis and can serve as potential drugs that can form the basis of treating mucormycosis disease.Communicated by Ramaswamy H. Sarma.
Insights
This study identifies two potential new drugs, CID439153 and CID5289104, to combat mucormycosis, a deadly fungal infection. These compounds target the Glucose-Regulated Protein 78 (GRP78) receptor, offering hope for safer and more effective treatments.
Area of Science:
- Mycology
- Computational Biology
- Drug Discovery
Background:
- Mucormycosis presents a high mortality rate (50%) despite current therapies.
- Glucose-Regulated Protein 78 (GRP78) is a key host receptor exploited by common mucormycosis-causing fungi.
- Existing antifungal drugs have significant side effects, necessitating novel therapeutic agents.
Purpose of the Study:
- To identify novel drug candidates targeting GRP78 for mucormycosis treatment.
- To computationally screen existing drug libraries for potential inhibitors of GRP78.
- To evaluate the binding affinity and stability of identified compounds against GRP78.
Main Methods:
- High-throughput virtual screening of 8820 drugs from the DrugBank library against GRP78.
- Selection of top compounds based on binding energies compared to a reference molecule.
- Molecular dynamic (MD) simulations using AMBER to assess the stability of lead compounds.
Main Results:
- Ten compounds showed promising binding energies against GRP78.
- Two compounds, CID439153 and CID5289104, demonstrated significant inhibitory potential.
- MD simulations confirmed the stability of these compounds within the GRP78 active site.
Conclusions:
- CID439153 and CID5289104 are proposed as potential therapeutic agents against mucormycosis.
- These compounds offer a promising basis for developing new treatments with potentially fewer side effects.
- Targeting GRP78 represents a viable strategy for combating this invasive fungal infection.
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