Identification of potential anti-mucor agents by targeting endothelial cell receptor glucose-regulated protein-78 using in silico approach

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