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盖列-8N-选择性4-哈洛菲尼尔弗塔拉齐诺-Galactals双π-堆在一个独特的口袋

Sjors van Klaveren^1,2, Mujtaba Hassan¹, Maria Håkansson³

¹Department of Chemistry, Faculty of Science, Lund University, Naturvetarvägen 14, 223 62, Lund, Sweden.

ACS medicinal chemistry letters

|August 14, 2024

概括

研究人员开发了针对加勒-8的选择性抑制剂,该蛋白质具有两个碳水化合物识别域 (CRD). 这些新型的甘氨基基-异环混合体对研究加勒-8生物学和潜在的治疗应用有很大的希望.

科学领域:

生物化学生物化学
药用化学医学化学
结构生物学结构生物学

背景情况:

盖莱克-8具有两个不同的碳水化合物识别域 (CRD).
针对特定CRD的有针对性的抑制对于理解galectin-8的功能和开发治疗方法至关重要.

研究的目的:

设计和发现针对加勒-8的碳水化合物识别领域的强效和选择性抑制剂.
开发用于galectin-8生物学研究和潜在药物开发的工具化合物.

主要方法:

基因对比-异环混合联体的结构导向设计.
生物化学测试以确定结合亲和力 (K_d) 和对各种加勒的选择性.
在高分辨率 (1.30 Å) 的X射线晶体学阐明联体蛋白相互作用.
在体外ADME (吸收,分布,新陈代谢,分泌) 研究,包括LogD,透性和稳定性评估.

主要成果:

一种4-(p-bromophenyl) phthalazinone衍生物证明了34μM的K_d对于加勒-8N (N-终端CRD).
这种化合物具有很高的选择性,没有与加勒-8C和其他测试过的加勒结合,比加勒-4C具有40倍以上的选择性.
X射线结构揭示了加勒-8N特定子口袋内的特定相互作用,解释了观察到的选择性.
观察到有利的物理化学特性 (LogD) 和良好的被动透性.
证实了有前途的化学,微体和血稳定性.

结论:

新型甘氨基基-异环杂交物是加勒-8N的强效和选择性抑制剂.
已识别的化合物作为有价值的工具化合物,用于galectin-8研究.
这些分子代表了在药物发现中进行打击到的优化有前途的候选人.

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