Novel Findings of Anti-Filarial Drug Target and Structure-Based Virtual Screening for Drug Discovery

Abstract

Lymphatic filariasis and onchocerciasis caused by filarial nematodes are important diseases leading to considerable morbidity throughout tropical countries. Diethylcarbamazine (DEC), albendazole (ALB), and ivermectin (IVM) used in massive drug administration are not highly effective in killing the long-lived adult worms, and there is demand for the development of novel macrofilaricidal drugs affecting new molecular targets. A Ca2+ binding protein, calumenin, was identified as a novel and nematode-specific drug target for filariasis, due to its involvement in fertility and cuticle development in nematodes. As sterilizing and killing effects of the adult worms are considered to be ideal profiles of new drugs, calumenin could be an eligible drug target. Indeed, the Caenorhabditis elegans mutant model of calumenin exhibited enhanced drug acceptability to both microfilaricidal drugs (ALB and IVM) even at the adult stage, proving the roles of the nematode cuticle in efficient drug entry. Molecular modeling revealed that structural features of calumenin were only conserved among nematodes (C. elegans, Brugia malayi, and Onchocerca volvulus). Structural conservation and the specificity of nematode calumenins enabled the development of drugs with good target selectivity between parasites and human hosts. Structure-based virtual screening resulted in the discovery of itraconazole (ITC), an inhibitor of sterol biosynthesis, as a nematode calumenin-targeting ligand. The inhibitory potential of ITC was tested using a nematode mutant model of calumenin.

In Silico Molecular Docking and In Vivo Validation with Caenorhabditis elegans to Discover Molecular Initiating Events in Adverse Outcome Pathway Framework: Case Study on Endocrine-Disrupting Chemicals with Estrogen and Androgen Receptors

“…These results appear to be very similar to those in human receptors, suggesting that our C. elegans models can surrogate the human receptors well. Although the binding affinity of NHR-14 was generally higher than the binding affinity of NHR-69, the rank-order of binding affinity is more important in the molecular docking study than the binding affinity itself, because the scoring function is different for each docking software [ 35 , 36 ].…”

Calumenin, a Ca2+ Binding Protein, Is Required for Dauer Formation in Caenorhabditis elegans

“…C. elegans has one homolog of calumenin and has been reported to function in various Ca 2+ -regulated behaviors [ 26 ]. C. elegans calumenin has also been proposed as a potential drug target for human-infective nematodes (filarial worms) due to its implication in normal cuticle development [ 41 ].…”