通过基于药剂的虚拟查来识别潜在的针对阿尔茨海默病的多目标化合物
Géssica Oliveira Mendes1, Moysés Fagundes de Araújo Neto1, Deyse Brito Barbosa1
1Laboratory of Molecular Modeling, Department of Health, State University of Feira de Santana, Feira de Santana 44036-900, BA, Brazil.
Pharmaceuticals (Basel, Switzerland)
|December 23, 2023
概括
这项研究确定了新的多用途化合物,它们同时抑制了与阿尔茨海默病 (AD) 病原发生有关的关键酶,为开发更有效的AD治疗提供了有希望的途径.
科学领域:
- 神经科学是一个神经科学.
- 药理学 药理学是指药理学的学科.
- 计算化学计算化学
背景情况:
- 阿尔茨海默病 (AD) 是导致痴呆的主要原因,其特点是由于胆固醇缺乏,β-粉样蛋白斑块和陶蛋白积累而导致认知能力下降.
- 目前的阿尔茨海默病治疗提供了症状缓解与显著的副作用,突出强调迫切需要疾病修饰疗法.
- 抑制乙胆酶 (AChE),丁胆酶 (BChE) 和β-分泌酶1 (BACE-1) 是阿尔茨海默病的关键治疗点.
研究的目的:
- 发现具有潜力同时抑制ACHE,BCHE和BACE-1的新型多用途化合物.
- 确定可以解决阿尔茨海默病多种病理途径的候选药物.
- 开发可以预防疾病进展和改善患者存活率的化合物.
主要方法:
- 虚拟层次查使用药法模型对BACE-1和双抑制剂的ACHE/BChE.使用.
- 根据BACE-1和双重ACHE/BChE抑制的QFIT分数对214,446个分子进行过.
- 对所选化合物的分子对接,物理化学和毒理学评估.
主要成果:
- 三种化合物 (ZINC45068352,ZINC03873986,ZINC71787288) 显示与药理模型相适应.
- ZINC03873986被优先考虑进一步验证,包括活性测试和结构-活性关系 (SAR) 研究.
- 这项研究成功地过了大量的化学库,以确定AD的有希望的多目标抑制剂.
结论:
- 这些已识别的化合物代表了开发下一代阿尔茨海默氏症治疗方法的有希望的线索.
- 同时抑制ACHE,BCHE和BACE-1为针对AD的多向药物设计提供了可行的策略.
- 进一步的实验验证和优化是有必要的,以推进这些候选人临床应用.
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