靶向PLK1 polo-box结构域的新型有效肽抑制剂的鉴定:基于结构的药效团建模、虚拟筛选、分子对接、分子动力学研究和生物学评价。

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Hong Zhou, Lixia Guan, Guoqiang Lin, Xiaotian Yang, Xingxia Zhang, Yejun Si, Yanming Zhang, Juan Chen
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引用次数: 0

摘要

多发性骨髓瘤是一种血液系统恶性肿瘤,PLK1在细胞中过表达与预后不良相关,提示PLK1是一种潜在的治疗靶点。在这项研究中,我们通过综合虚拟筛选策略发现了5个靶向PLK1 polo box domain (PBD)的肽(PLs 1-5)。MST实验证实,PLs 1-5对PLK1具有较强的结合亲和力,特别是PL-1 (Kd = 3.11±0.05 nM)。同时,激酶选择性实验表明,PL-1对其他一组激酶没有明显的抑制作用。分子动力学模拟进一步证明了PL-1和PLK1复合物的结构稳定性。值得注意的是,PL-1对U266多发性骨髓瘤细胞具有较强的抗增殖作用(IC50 = 0.09±0.01µM)。PL-1表现出较高的细胞内摄取能力。此外,PL-1在人血清和肝微粒体中具有良好的生物稳定性。总之,PL-1是一种有效的、高选择性的抗肿瘤药物,对多发性骨髓瘤具有相当大的治疗前景。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identification of novel potent peptide inhibitors targeting the polo-box domain of PLK1: structure-based pharmacophore modelling, virtual screening, molecular docking, molecular dynamics study and biological evaluation.

Multiple myeloma, a hematological malignancy, shows PLK1 overexpression in cells correlates with poor prognosis, suggesting PLK1 as a potential therapeutic target. In this study, we discovered five peptides (PLs 1-5) targeting the polo box domain (PBD) of PLK1 through an integrated virtual screening strategy. MST assays confirmed that PLs 1-5 had strong binding affinity for PLK1, especially PL-1 (Kd = 3.11 ± 0.05 nM). Meanwhile, the kinase selectivity assay showed that the PL-1 had no significant inhibitory effects on a panel of other kinases. Molecular dynamics simulation further demonstrated the structural stability of PL-1 and PLK1 complex. Notably, PL-1 displayed potent antiproliferative efficacy against U266 multiple myeloma cells (IC50 = 0.09 ± 0.01 µM). PL-1 showed high intracellular uptake capacity. In addition, PL-1 exhibited good biostability in human serum and liver microsomes. Taken together, PL-1 is a potent and highly selective antitumor agent with considerable therapeutic promise for multiple myeloma.

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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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