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通过DNA编码的自然产品库查快速发现CD38抑制剂

Xinyu Shi¹, Ze Liang¹, Wentao Meng¹

¹State Key Laboratory of Microbial Technology, School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China.

Molecules (Basel, Switzerland)

|March 14, 2026

概括

通过DNA编码的图书馆技术确定了芬达和弗卢本达是CD38酶的新型小分子抑制剂. 这些化合物显示出治疗CD38相关疾病的潜力,如多发性骨髓瘤和神经退行症.

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:

CD38是NAD+代谢和信号传递中的关键酶,涉及多发性骨髓瘤,代谢衰退和神经退行性疾病.
目前的CD38抑制剂,像单克隆抗体一样,有局限性,这导致需要新的小分子替代品.

研究的目的:

通过使用DNA编码库 (DEL) 技术发现新的小分子CD38抑制剂.
为了验证已识别的抑制剂的疗效并阐明它们的作用机制.

主要方法:

一个DEL库 (>100,000个化合物) 的高通量选与人类复合CD38.8对抗.
表面等离子体共振 (SPR) 用于结合确认,酶测试用于活性抑制,以及结构-活性关系 (SAR) 分析.
分子对接和分子动力学 (MD) 模拟以确定结合机制.

主要成果:

确定了八种打击化合物,包括重新使用的抗寄生虫药物芬班达.
SPR证实了直接结合 (KD:7.74 × 10−5 M 到 2.15 × 10−4 M).
班达和flubendazole证明了对CD38酶和环酶活动的剂量依赖抑制,而flubendazole显示IC₅₀值分别为14.78μM和26.31μM.

结论:

德尔技术是发现CD38抑制剂的有效平台.
班达和班达代表了开发新疗法治疗CD38相关疾病的有前途的支架.
范德瓦尔斯相互作用和保存的芳香残留是CD38活性部位中小分子结合的关键.

关键词:

CD38 CD38 CD38 CD38 CD38 CD38 CD38 CD38 CD38 CD38 CD38 CD38 CD38 CD38 DNA编码的图书馆 (DEL)NAD+代谢 NAD+的代谢酶活性的酶活性.分子对接的分子对接.小分子抑制剂小分子抑制剂结构-活动关系 (SAR)

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