碎片合并,生长和结合识别了利什曼病的新型试氨降解酶抑制剂
Cécile Exertier1, Alessandra Salerno2, Lorenzo Antonelli3
1Institute of Molecular Biology and Pathology (IBPM) of the National Research Council of Italy (CNR), c/o Department of Biochemical Sciences, Sapienza University of Rome, Piazzale A. Moro 5, Roma 00185, Italy.
Journal of medicinal chemistry
|January 2, 2024
概括
基于碎片的药物发现成功地发现了三甲减少酶 (TR) 的新抑制剂,这是莱什曼病治疗的关键标. 这种方法产生了有前途的化合物,证明了开发新型抗莱什曼病治疗的潜力.
科学领域:
- 药用化学 医学化学
- 药物发现 药物发现 药物发现
- 寄生虫学的寄生虫学
背景情况:
- 特里巴诺氨酸减少酶 (TR) 是对莱什曼病的验证药物标.
- 开发强大的TR抑制剂仍然是药物发现的重大挑战.
研究的目的:
- 应用基于片段的药物发现 (FBDD) 策略,以识别试氨酸减少酶的新兴抑制剂.
- 通过基于结构和带的方法指导药物化学的努力.
主要方法:
- 碎片选和结晶学分析确定了最初的碎片.
- 结构-活性关系 (SAR) 研究使用in silico和in vitro测试进行.
- 结晶学证实了优化的化合物与TR的结合.
主要成果:
- FBDD产生了一系列新的TR抑制剂 (化合物4-14).
- 化合物10表现出最强大的TR抑制 (Ki = 0.2μM).
- 化合物9在体外和体外表现出优越的活性.
结论:
- FBDD是一种可行的策略,可以针对具有挑战性的寄生酶,如TR.
- 这些已识别的化合物显示了利什曼病药物开发的潜力,尽管需要进一步优化选择性.
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