Structure-Based Optimization of TBK1 Inhibitors

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-03-31 DOI:10.1021/acsmedchemlett.4c0063610.1021/acsmedchemlett.4c00636

Wenxuan Sun, Yuting Xie, Qiancheng Xia, Yuanxun Wang, Xiangbing Qi* and Niu Huang*,

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Abstract

TBK1 is a crucial kinase involved in immunity, inflammation, and autophagy with dysregulation linked to various diseases, making it a potential therapeutic target. In this study, we applied a structure-based lead optimization approach to design potent and selective TBK1 inhibitors. A focused virtual library containing over 5,000 compounds was constructed, sampled, and refined within the kinase binding site, followed by a 10 ns molecular dynamics simulation for each modeled binding complex. Based on MM/PBSA binding free energies and structural clustering, we selected 14 structurally diverse compounds for chemical synthesis and biological assays. This strategy yielded a potent TBK1 inhibitor (IC₅₀ = 775 pM) from an initial hit of 19.57 μM. This inhibitor features a novel scaffold and exhibits excellent enzymatic inhibition. Furthermore, it enhances immune-mediated cytotoxicity without exhibiting cytotoxicity when used as a single agent. These findings provide a foundation for the development of targeted therapies for the treatment of TBK1-associated diseases.

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TBK1抑制剂的结构优化

TBK1是一种重要的激酶，参与免疫、炎症和自噬，与各种疾病相关的失调，使其成为潜在的治疗靶点。在这项研究中，我们应用了基于结构的先导优化方法来设计有效的和选择性的TBK1抑制剂。在激酶结合位点内构建了一个包含5000多个化合物的集中虚拟文库，对每个模拟的结合复合物进行了10 ns的分子动力学模拟。基于MM/PBSA结合自由能和结构聚类，我们选择了14个结构多样的化合物进行化学合成和生物实验。该策略产生了一种有效的TBK1抑制剂（IC50 = 775 pM），初始深度为19.57 μM。该抑制剂具有新颖的支架结构，具有良好的酶抑制作用。此外，它可以增强免疫介导的细胞毒性，而不表现出细胞毒性。这些发现为开发tbk1相关疾病的靶向治疗提供了基础。

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

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.