基于结构的药物重新定位和针对Mycobacterium tuberculosis的LigaseD的抑制剂的实验验证实
Ayushi Saini1, Aishik Sil1, Satyajit Beura1
1Department of Bioscience and Biotechnology, IIT Kharagpur, West Bengal, India.
Archives of biochemistry and biophysics
|October 30, 2025
概括
像印尼纳维尔这样的重用药物可以抑制Mycobacterium结核病中的DNA修复,提供对休眠和耐药感染的新策略.
科学领域:
- 微生物学 微生物学
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 结核菌菌 (Mycobacterium tuberculosis,Mtb) 构成一个重大的全球卫生挑战,其药物耐药性及其在宿主压力下生存的能力加剧了这一问题.
- Mtb采用DNA修复机制,包括非同类末端连接 (NHEJ),以提高弹性,特别是在休眠期间.
- 酶D酶的酶域 (LigDom) 对于NHEJ至关重要,可保存,并且是一种潜在的药物标.
研究的目的:
- 确定FDA批准的药物,可以抑制Mtb的DNA修复途径,特别针对LigDom.
- 评估针对Mtb的已识别的抑制剂的治疗潜力,特别是在模仿宿主诱导的压力条件下.
主要方法:
- 基于结构的药物重定位屏幕对抗LigDom.对FDA批准的药物进行重定位.
- 分子动力学模拟用于分析药物向相互作用和复杂稳定性.
- 使用艾滋病毒蛋白酶抑制剂Indinavir进行实验验证,评估其对LigDom活性和Mtb存活率的影响.
主要成果:
- 通过药物重新定位,L-756423被确定为一种强大的LigDom抑制剂.
- 分子动力学模拟显示稳定的LigDom-Lig-756423复合体具有潜在的OB域移动性.
- 印纳维尔可以竞争性地抑制ATP与LigDom的结合,阻断腺和损害DNA修复.
- 印纳维尔治疗在氧化应激下降低了Mtb存活率,证实了NHEJ受损.
结论:
- 美国食品和药物管理局批准的药物,如印尼纳维尔,可以有效地抑制 Mtb.中的必不可少的DNA修复酶 LigaseD.
- 向LigDom是一种有前途的治疗策略,用于对抗潜伏性和耐药结核病.
- 对于结核病治疗的发展,需要对印尼纳维尔和类似化合物的进一步研究.
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