基于机器学习和结构的虚拟选,以选择酸衍生物作为 DHFR-TS 抑制剂
Maria Camila Muñoz-Vega1,2, Sofía López-Hernández1, Adrián Sierra-Chavarro1
1Department of Chemical Engineering, Universidad ECCI, Bogotá, Distrito Capital 111311, Colombia.
Molecules (Basel, Switzerland)
|January 11, 2024
概括
研究人员从Asteraceae植物代谢物中确定了Leishmania主要二叶酸减少酶-甲基酸合成酶 (LmDHFR-TS) 的强有力的抑制剂. 这些化合物显示出开发新的抗莱什曼病药物来对抗这种被忽视的热带疾病的希望.
科学领域:
- 药用化学 医学化学
- 寄生虫学的寄生虫学
- 药物发现 药物发现 药物发现
背景情况:
- 酶二酸盐减少酶-甲基酸合成酶 (DHFR-TS) 对于大莱什曼病 (LmDHFR-TS) 的DNA合成至关重要,使其成为抗莱什曼病治疗的关键标.
- 开发针对LmDHFR-TS的新型抑制剂对于对抗被忽视的热带疾病莱什曼病至关重要.
研究的目的:
- 来识别从二次代谢基因的数据库中发现LmDHFR-TS的潜在抑制剂,这些代谢基因来自Asteraceae家族中的肉酸.
- 评估已识别的化合物的 in silico 和 in vitro 疗效和对 LmDHFR-TS 的选择性.
主要方法:
- 基于联体/结构的综合虚拟选方法被用于从314种Asteraceae二次代谢物中识别潜在的LmDHFR-TS抑制剂.
- 进行了分子动力学模拟,以分析酶活性部位内的有希望的命中化合物的结合模式和稳定性.
- 进行了体外测试,以确定对LmDHFR-TS和人类DHFR (HsDHFR) 的排名第一的化合物的抑制活性 (IC50) 和选择性指数 (SI).
主要成果:
- 通过虚拟选,三种化合物 - - 石酸 (237),二基基宁 (306) 和分离醇A (308) - - 被确定为有希望的命中药物.
- 在体外测试证实了针对LmDHFR-TS的测试化合物的IC50值在6.1至10.1μM之间的抑制活性.
- 灵306和308具有较高的选择性,与参考药物甲托雷克萨特相比,其SI值更高,而其他测试的黄类糖化物活性较低.
结论:
- 来自Asteraceae家族的C6C3混合型布提罗拉克联体,特别是二基因因 (306) 和单抗醇A (308),是LmDHFR-TS.的强效和选择性抑制剂.
- 这些发现突显了这些类化合物作为化合物的潜力,用于开发新的抗莱什曼病化疗.
- 对这些化合物的进一步研究可能会导致利什曼病的有效治疗方法,解决对被忽视的热带疾病的关键需求.
关键词:
星座科 (Asteraceae) 是一个植物.在DHFR-TS中使用.莱什曼尼亚 (Leishmania) 是一种病.黄类化合物 黄类化合物林南斯 林南斯 林南斯机器学习是机器学习.自然产品是自然产品的产品.更多相关视频
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