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亲和选择质谱与生物物理验证相结合,使CHI3L1结合剂的概念验证发现成为可能

Baljit Kaur¹, Hossam Nada¹, Moustafa Gabr¹

¹Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, NY 10065, USA.

Biochemical and biophysical research communications

|October 16, 2025

概括

研究人员确定了第一个小分子,化合物A9,它与酸酶-3样蛋白1 (CHI3L1) 结合. 这一突破利用亲和选择质谱法 (AS-MS) 准这种以前无法治疗的蛋白质,为新疗法铺平了道路.

科学领域:

生物化学生物化学
药用化学医学化学
药物发现药物发现药物发现

背景情况:

基因酶-3样蛋白1 (CHI3L1) 是一种关键的细胞外糖蛋白,参与瘤进展,免疫抑制和纤维化.
它在疾病中的作用使CHI3L1成为一个重要的治疗点,但它的细胞外性质对药物开发构成了挑战.

研究的目的:

为了研究CHI3L1.1.的化学可处理性.
使用高通量选方法识别能够与CHI3L1结合的小分子.

主要方法:

一个亲和选择质谱 (AS-MS) 工作流被用来选大约10,000个小分子的CHI3L1结合.
根据化学适用性优先考虑了命中事件,并使用微尺度热泳 (MST) 验证了候选人.
分子对接被用来阐明结合相互作用.

主要成果:

在AS-MS屏幕上发现了124个初始命中 (1.24%的命中率).
化合物A9在MST试验中证明了对CHI3L1的剂量依赖性结合,解离常数 (Kd) 为182±18μM.
分子对接证实了A9在CHI3L1的特定口袋内结合,涉及水和结合相互作用.

结论:

这项研究介绍了第一个通过AS-MS通过CHI3L1识别的小分子结合剂A9.
这些发现为化学参与CHI3L1建立了概念验证,为开发化学探针和优化治疗策略的基础提供了基础.

关键词:

亲和选择质谱法 (AS-MS) 是一种亲和选择质谱法.CHI3L1 的意思是药物发现药物发现小分子是小分子.

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