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整合催化C-N合到自编码库中,以加速命中发现

Edith van der Nol^1,2, Zhenshuo Luo¹, Qing Qing Gao¹

¹LACDR, Leiden University Leiden 2333 CC The Netherlands s.j.pomplun@lacdr.leidenuniv.nl.

RSC chemical biology

|March 13, 2026

概括

自编码库 (SEL) 为药物发现提供了无条码的方法,克服了DNA编码库 (DEL) 的局限性. 这项研究将布丘瓦尔德-哈特维格氨化物整合到SEL中,使得可以快速识别碳酸无水酶IX (CAIX) 的强 binders.

科学领域:

药用化学医学化学
化学生物学化学生物学
药物发现技术药物发现技术

背景情况:

DNA编码图书馆 (DEL) 对于命中发现具有强大功能,但面临着DNA兼容性和条形码复合不匹配的挑战.
自编码图书馆 (SEL) 提供了无条码的替代方案,提供了更大的灵活性和直接化学结构解码.
将SEL能力扩展到各种化学反应是扩大其在药物发现中的应用性至关重要的.

研究的目的:

将布丘瓦尔德-哈特维格的amination集成到自编码库 (SEL) 平台中.
使用这种新反应来构建和优化高多样性的SEL.
选一个大型SEL图书馆对碳酸无水酶IX (CAIX) 进行选,并确定有力的结合剂.

主要方法:

在SEL框架内优化Buchwald-Hartwig氨化反应条件.
综合和描述使用超过170个构建块的SELs.
基于MS/MS的解码 (SIRIUS-COMET) 的调整,用于从复杂混合物中准确识别命中.
对25725名成员的SEL图书馆进行对碳酸无水酶IX (CAIX) 的选.

主要成果:

在SEL平台中成功集成催化布丘瓦尔德-哈特维格氨化.
证明了高多样性的SEL建筑,有>170个建筑块.
在CAIX结合剂中丰富的特定构建模块的识别.
为CAIX发现了几种纳米分子亲和结合剂.

结论:

该SEL平台成功地扩展到包括多功能布丘瓦尔德-哈特维格氨基,显著增加了其化学空间.
优化的SEL方法与先进的解码相结合,使得高合成多功能性高效的命中发现.
这一进步加速了对强效药物的鉴定,以CAIX结合剂的发现为例.

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