通过基于结构的虚拟查发现了新的Schistosoma mansoni阿斯巴提尔蛋白酶抑制剂
Bárbara Figueira Gomes1, Mario Roberto Senger1, José Teófilo Moreira-Filho2
1Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Bioquímica Experimental e Computacional de Fármacos, Rio de Janeiro, RJ, Brasil.
Memorias do Instituto Oswaldo Cruz
|September 6, 2023
概括
研究人员确定了Schistosoma mansoni aspartic蛋白酶SmCD1的新型抑制剂,这是寄生虫血红蛋白消化中的关键酶. 这些化合物显示出开发针对这种被忽视的热带疾病的新型分裂杀菌药物的潜力.
科学领域:
- 寄生虫学的寄生虫学
- 药物发现 药物发现 药物发现
- 生物化学 生物化学
背景情况:
- 湿是一种被遗忘的热带疾病,由湿虫寄生虫引起,治疗选择有限,主要依赖于praziquantel (PZQ).
- 包括SmCD1在内的酸蛋白酶对于寄生虫的生存至关重要,特别是在血红蛋白消化过程中,这使得它们成为潜在的药物点.
研究的目的:
- 发现了新型的schistosoma mansoni亚斯巴达蛋白酶SMCD1.1.的抑制剂.
- 为了确定新的化学支架与schistosomicidal潜力.
主要方法:
- 一个化学库的基于结构的虚拟选.
- 对SmCD1,SmCD2和SmCD3进行同质建模.
- 使用重组酶和成年虫提取物进行酶分析.
- 对成年虫进行ex vivo测试和细胞毒性测试.
主要成果:
- 七种化合物被识别为对SmCD1.1的打击.
- 两个新的化学支架,化合物5和19,显示IC50值约为100μM.
- 化合物50对一个Schistosoma mansoni亚斯帕尔特蛋白酶 (SmCD2) 具有选择性,而不是哺乳动物酶.
- 化合物没有显著的细胞毒性或对成年虫的直接致命性.
结论:
- 已识别的抑制剂代表了开发新型分裂性杀菌药物的有希望的起点.
- 需要进一步优化,以提高抗 Schistosoma 寄生虫的功效和疗效.
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