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

Title
Novel Findings of Anti-Filarial Drug Target and Structure-Based Virtual Screening for Drug Discovery
Author
안주홍
Keywords
filariasis; molecular modeling; virtual screening; anti-filarial drug; calumenin; itraconazole
Issue Date
2018-11
Publisher
MDPI
Citation
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 19, no. 11, Article no. 3579
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.
URI
https://www.mdpi.com/1422-0067/19/11/3579https://repository.hanyang.ac.kr/handle/20.500.11754/120556
ISSN
1422-0067
DOI
10.3390/ijms19113579
Appears in Collections:
COLLEGE OF NATURAL SCIENCES[S](자연과학대학) > LIFE SCIENCE(생명과학과) > Articles
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