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用DNA编码的化学图书馆选择,然后用机器学习来发现WDR91的第一级小分子干体

Shabbir Ahmad¹, Jin Xu², Jianwen A Feng²

¹Structural Genomics Consortium, University of Toronto, Ontario M5G 1L7, Canada.

Journal of medicinal chemistry

|November 23, 2023

概括

研究人员确定了一种针对WD40重复含有蛋白91 (WDR91) 的选择性化合物,WDR91是内分体传输和病毒感染的关键因素. 这一发现为治疗开发提供了新的化学工具.

科学领域:

生物化学生物化学
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:

WD40重复含有蛋白91 (WDR91) 对于内体贩运至关重要,包括融合和回收.
WDR91已成为病毒感染中的重要宿主因素,突出其治疗相关性.

研究的目的:

发现针对WDR91的新型化学工具,用于潜在的治疗应用.
为了探索WDR91连接体的结构-活性关系.

主要方法:

用DNA编码的化学库 (DEL) 对WDR91.1.的WDR域进行选择.
来自Enamine REAL数据库的联体的机器学习预测.
表面等离子体共振 (SPR) 用于结合亲和度的确定.
共同晶体结构分析和质谱学用于共价 adduct 确认.

主要成果:

鉴定了一种选择性WDR91抑制剂,化合物1,其K_D为6 ± 2μM.
同晶体结构揭示化合物1与氨酸487.7附近的WDR91侧口袋结合.
发现了共价类型的18和19与确认的形形成.

结论:

已识别的化合物1,18和19作为WDR91.1.的有价值的化学探针.
结构和SAR洞察力促进了强大和选择性的WDR91调节器的设计.
这项研究为评估WDR91在病毒感染和其他疾病中的治疗潜力铺平了道路.

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