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计算机辅助分子设计和优化破坏APC-Asef相互作用的强抑制剂

Xuefei Wang^1,2, Zeqian Du³, Yuegui Guo⁴

¹Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.

Acta pharmaceutica Sinica. B

|June 3, 2024

概括

研究人员开发了针对APC-Asef相互作用的新型抑制剂,以对抗转移性结直肠癌 (CRC). 这些强效化合物在抑制肺转移方面表现出有效性,为CRC患者提供了有前途的治疗途径.

科学领域:

在瘤学瘤学.
药用化学医学化学
分子生物学分子生物学

背景情况:

结肠直肠癌 (CRC) 是全球癌症死亡的主要原因,大约20%的患者被诊断为转移性疾病 (mCRC).
腺多样性肠杆菌 (APC) 和SREP表达激活剂 (Asef) 之间的相互作用是mCRC的验证治疗标.
开发针对这种相互作用的有效和安全药物仍然是一个重大挑战.

研究的目的:

识别和优化针对潜在的mCRC治疗APC-Asef相互作用的新型抑制剂.
调查抑制剂有效性的结构基础及其作用机制.
在临床前模型中评估这些新型抑制剂的治疗潜力.

主要方法:

利用基于之前报告的MAI抑制剂的新型结构支架.
采用ONIOM (我们自己的N层集成分子轨道和分子力学) 基于模型的优化.
进行了抑制活性的实验评估,共晶结构分析和体外/体内研究.

主要成果:

与父母化合物相比,与优化的抑制剂相比,功效增加了24倍.
验证了双层 ππ 堆叠相互作用对于通过共晶结构来稳定抑制剂的重要性.
在CRC模型中通过破坏APC-Asef相互作用来证明抑制肺转移.

结论:

基于MAI的新型抑制剂对APC-Asef介导的CRC具有显著增强的功效和有效性.
这些结构性见解为开发用于CRC治疗的药物样分子提供了基础.
这些发现提供了一个有希望的策略,通过破坏APC-Asef相互作用来向转移性结直肠癌.

关键词:

这就是APC-Asef.计算机辅助分子设计转移性结直肠癌是什么意思在 ONIOM 模型中.作为一种类仿制剂,它具有类仿制性.π‒π 堆叠方式

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