药物重新定位为 LIR motif p62/SQSTM1 蛋白确定了潜在的自噬抑制剂。

IF 2.6 4区 生物学 Q2 BIOLOGY Computational Biology and Chemistry Pub Date : 2024-10-03 DOI:10.1016/j.compbiolchem.2024.108235
Narjes Asghari , Ali Kian Saei , Marco Cordani , Zahra Nayeri , Mohammad Amin Moosavi
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引用次数: 0

摘要

自噬是在应激条件下降解受损细胞器和蛋白质的关键细胞过程,已被证明有助于肿瘤的存活和耐药性。Sequestosome-1(SQSTM1/p62)是一种自噬受体,它通过 LC3 结合区(LIR)与其结合伙伴相互作用。p62 蛋白因其在选择性自噬中的关键作用而成为备受研究的靶标。在本研究中,我们旨在找出与 p62 的 LIR 矩阵结合并抑制其 LIR 功能的 FDA 批准药物,这些药物可能是调节自噬的有用靶点。为此,我们利用生物数据预测了 p62 蛋白的同源模型,并使用 Molegro Virtual Docker 和 PyRx 软件进行了对接分析。我们使用 ProTox-II 服务器进一步评估了药物的毒性特征,并对确定的有效候选药物进行了动力学模拟。结果显示,卡那霉素、velpatasvir、verteporfin 和 temoporfin 能显著减少 LIR 与 p62 蛋白的结合。最后,我们通过实验证实,卡那霉素能抑制乳腺癌 MCF-7 和 MDA-MB 231 细胞中与自噬相关的酸性囊泡的形成。这些重新定位的药物可能是临床治疗中新型的自噬调节剂,值得进一步研究。
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Drug repositioning identifies potential autophagy inhibitors for the LIR motif p62/SQSTM1 protein
Autophagy is a critical cellular process for degrading damaged organelles and proteins under stressful conditions and has casually been shown to contribute to tumor survival and drug resistance. Sequestosome-1 (SQSTM1/p62) is an autophagy receptor that interacts with its binding partners via the LC3-interacting region (LIR). The p62 protein has been a highly researched target for its critical role in selective autophagy. In this study, we aimed to identify FDA-approved drugs that bind to the LIR motif of p62 and inhibit its LIR function, which could be useful targets for modulating autophagy. To this, the homology model of the p62 protein was predicted using biological data, and docking analysis was performed using Molegro Virtual Docker and PyRx softwares. We further assessed the toxicity profile of the drugs using the ProTox-II server and performed dynamics simulations on the effective candidate drugs identified. The results revealed that the kanamycin, velpatasvir, verteporfin, and temoporfin significantly decreased the binding of LIR to the p62 protein. Finally, we experimentally confirmed that Kanamycin can inhibit autophagy-associated acidic vesicular formation in breast cancer MCF-7 and MDA-MB 231 cells. These repositioned drugs may represent novel autophagy modulators in clinical management, warranting further investigation.
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来源期刊
Computational Biology and Chemistry
Computational Biology and Chemistry 生物-计算机:跨学科应用
CiteScore
6.10
自引率
3.20%
发文量
142
审稿时长
24 days
期刊介绍: Computational Biology and Chemistry publishes original research papers and review articles in all areas of computational life sciences. High quality research contributions with a major computational component in the areas of nucleic acid and protein sequence research, molecular evolution, molecular genetics (functional genomics and proteomics), theory and practice of either biology-specific or chemical-biology-specific modeling, and structural biology of nucleic acids and proteins are particularly welcome. Exceptionally high quality research work in bioinformatics, systems biology, ecology, computational pharmacology, metabolism, biomedical engineering, epidemiology, and statistical genetics will also be considered. Given their inherent uncertainty, protein modeling and molecular docking studies should be thoroughly validated. In the absence of experimental results for validation, the use of molecular dynamics simulations along with detailed free energy calculations, for example, should be used as complementary techniques to support the major conclusions. Submissions of premature modeling exercises without additional biological insights will not be considered. Review articles will generally be commissioned by the editors and should not be submitted to the journal without explicit invitation. However prospective authors are welcome to send a brief (one to three pages) synopsis, which will be evaluated by the editors.
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