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合成,动力学研究和二核酸聚酸盐衍生物的QSAR作为人类AK1抑制剂

Anna Kozakiewicz-Piekarz¹, Magdalena Grzegórska¹, Kamil Ziemkiewicz²

¹Faculty of Chemistry, Nicolaus Copernicus University in Toruń, Gagarina 7 87-100 Torun, Poland.

Bioorganic chemistry

|May 14, 2024

概括

腺酸酶 (AK) 对于细胞能量至关重要. 这项研究测试了二核酸多酸盐作为人类AK1的抑制剂,发现强效化合物并开发未来药物发现的预测模型.

科学领域:

生物化学生物化学
酶学是一种酶学.
药用化学医学化学

背景情况:

腺酸酶 (AK) 调节细胞腺核酸的稳态和能量代谢.
AK是癌症和神经退行等疾病的潜在治疗标.
由于缺乏经批准的针对AK的药物,限制了对其病理作用的研究.

研究的目的:

评估各种丁核酸聚酸衍生物对人类腺酸激酶异酶1 (hAK1) 的抑制作用.
通过分子对接和QSAR分析了解这些抑制剂的结构-活性关系.
开发用于识别新型hAK1调节器的预测模型.

主要方法:

合成和商业收购19种二核酸聚酸衍生物.
试验室酶分析测试以确定化合物对hAK1.1的抑制活性 (IC50值).
分子对接模拟用于预测结合相互作用.
使用PLS回归来构建预测模型的定量结构-活动关系 (QSAR) 分析.

主要成果:

所有测试的二核酸多酸盐都以不同的效率抑制了hAK1活性.
三种化合物的IC50值低于1μM,其中P1-(5'-adenosyl) P5-(5'-adenosyl) 五酸盐 (Ap5A) 是最强大的抑制剂.
QSAR模型显示出良好的预测能力 (R2=0.931,Q2=0.854对于模型1;R2=0.913,Q2=0.848对于模型2).

结论:

丁核酸多酸盐是hAK1.1的有效抑制剂.
分子对接和QSAR分析提供了关于抑制剂-标相互作用的见解.
开发的QSAR模型可以指导用于治疗应用的更强效和选择性的腺酸酶抑制剂的设计.

关键词:

丁核酸多酸盐是一种多酸盐.酶抑制可以抑制酶.人类腺酸酶酶异酶1 分子对接是分子对接.在QSAR中使用QSAR.

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