Identification of a novel Aurora B inhibitor using the AI-driven drug screening and docking-based traditional screening

IF 3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-09-27 DOI:10.1016/j.bmc.2025.118423

Jiayuan Ye , Nan Chen , Yixiang Zhu , Yana Xu , Chenghao Pan , Yaojiang Xu

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Abstract

Aurora B, a subtype of Aurora kinases that functions as a serine/threonine kinase, playing a vital role in the process of mitosis, is often overexpressed in certain tumor cells leading to tumorigenesis and progression. Therefore, the development of small molecule inhibitors targeting Aurora B holds promise for providing new options for some cancer patients. In this study, we efficiently screened 4 compounds from MCE compound database using a combination of machine learning-based screening and structure-based screening. The results showed that 2 compounds exhibited strong Aurora B inhibitory activity in a homogeneous time-resolved fluorescence (HTRF) assay, indicating a high hit rate for this screening method. Among them, compound 4 demonstrated optimal inhibitory activity against Aurora B, with an IC₅₀ value of 15.54 nM, comparable to Aurora B inhibitors that have entered clinical trials. In vitro experiments indicated that compound 4 effectively inhibited Huh-7 and Huh-6 cells, with IC₅₀ values of 0.9 μM and 1.8 μM, respectively. Molecular dynamics simulation results revealed that the compound binds to the ATP binding pocket of Aurora B, forming hydrogen bond interactions with Glu171 and Glu220, salt bridges with Asp234 and Glu177, and a pi-cation interaction with Arg97. In summary, by integrating multi-modal screening approaches, we successfully identified a potent Aurora B inhibitor with in vitro antitumor activity, providing lead compounds for subsequent drug development.

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利用人工智能驱动的药物筛选和基于对接的传统筛选鉴定一种新的Aurora B抑制剂。

Aurora B是Aurora激酶的一种亚型，作为丝氨酸/苏氨酸激酶，在有丝分裂过程中起着至关重要的作用，在某些肿瘤细胞中经常过度表达，导致肿瘤发生和进展。因此，开发针对Aurora B的小分子抑制剂有望为一些癌症患者提供新的选择。在本研究中，我们采用基于机器学习的筛选和基于结构的筛选相结合的方法，从MCE化合物数据库中高效筛选了4种化合物。结果表明，2个化合物在均匀时间分辨荧光（HTRF）实验中表现出较强的Aurora B抑制活性，表明该筛选方法的命中率较高。其中，化合物4对Aurora B的抑制活性最佳，IC50值为15.54 nM，与已进入临床试验的Aurora B抑制剂相当。体外实验表明，化合物4能有效抑制Huh-7和Huh-6细胞，IC50值分别为0.9 μM和1.8 μM。分子动力学模拟结果表明，该化合物与Aurora B的ATP结合口袋结合，与Glu171和Glu220形成氢键相互作用，与Asp234和Glu177形成盐桥，与Arg97形成π -阳离子相互作用。综上所述，通过整合多模式筛选方法，我们成功鉴定了一种具有体外抗肿瘤活性的强效Aurora B抑制剂，为后续药物开发提供了先导化合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.