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首页> 美国卫生研究院文献>International Journal of Molecular Sciences >Novel Findings of Anti-Filarial Drug Target and Structure-Based Virtual Screening for Drug Discovery
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Novel Findings of Anti-Filarial Drug Target and Structure-Based Virtual Screening for Drug Discovery

机译：抗丝虫药物靶标的新发现和基于结构的药物发现虚拟筛选

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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.
机译：丝虫线虫引起的淋巴丝虫病和盘尾丝虫病是导致整个热带国家大量发病的重要疾病。在大规模药物管理中使用的二乙基卡巴马嗪（DEC），阿苯达唑（ALB）和伊维菌素（IVM）在杀死长寿命的成年蠕虫方面不是非常有效，因此需要开发影响新分子靶标的新型大杀线虫药物。 Ca 2 + 结合蛋白calumenin被确定为新型的，针对线虫病的线虫病药物靶标，因为它参与了线虫的生育能力和表皮发育。由于成虫蠕虫的杀菌和杀灭作用被认为是新药的理想特征，因此Calumenin可能是合格的药物靶标。的确，即使在成年期，钙黄绿素的秀丽隐杆线虫突变体模型也显示出对两种微丝杀虫药（ALB和IVM）的药物可接受性增强，证明了线虫表皮在有效药物进入中的作用。分子建模表明，Calumenin的结构特征仅在线虫（秀丽隐杆线虫，马来亚布鲁格氏菌和小肠盘尾虫）中保守。线虫Calumenins的结构保守性和特异性使得能够开发出在寄生虫和人类宿主之间具有良好靶标选择性的药物。基于结构的虚拟筛选导致发现了伊曲康唑（ITC），它是一种固醇生物合成抑制剂，是一种靶向线虫钙黄素的配体。使用calumenin的线虫突变体模型测试了ITC的抑制潜力。

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