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使用新的二甲基以太抑制剂探索InhA基质结合部位的可塑性

Rasoul Tamhaev¹, Emeline Grosjean², Hikmat Ahamed²

¹Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (LSPCMIB), UMR 5068, CNRS, Université Toulouse III - Paul Sabatier (UT3), Toulouse, France; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3), Toulouse, France.

Bioorganic chemistry

|December 21, 2023

概括

研究人员设计了新型的直接利乙烯抑制剂,准了必不可少的Mycobacterium结核病InhA蛋白. 化合物21表现出显著的InhA抑制,提供了一种有前途的新策略来对抗结核病.

科学领域:

药用化学医学化学
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:

结核病 (TB) 是由Mycobacterium tuberculosis (Mtb) 引起的,在全球范围内影响着数百万人.
InhA是Mtb的验证治疗标,对其生存至关重要.
现有的抑制剂通常需要被KatG激活,这就造成了局限性.

研究的目的:

设计和合成InhA的新型直接利乙烯抑制剂.
开发不需要KatG激活的化合物.
探索结核病的新治疗策略.

主要方法:

合成了11种新型的二甲基乙烯化合物,其中包括3种药理.
在体外评估对InhA的抑制活性.
一种化合物与InhA/NAD+共同结晶,用于结构分析.

主要成果:

化合物21,5-----------------------------------------------------------------------------------------------------------------------------------------------------
晶体结构显示,21号化合物完全占据了InhA基质结合部位和小门户.
抑制剂是为直接作用而设计的,绕过了KatG激活的需要.

结论:

针对InhA的新型直接利乙烯抑制剂已成功设计和合成.
化合物21代表了开发新的抗结核药物的有希望的领先.
结构洞察力为进一步优化InhA抑制剂提供了基础.

关键词:

迪亚利尔乙烯的使用方法在hAAA中.抑制剂抑制剂抑制剂小门户小门户小门户结核病是一种疾病.在X射线晶体学.

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