Discovery of novel dual-targeting inhibitors against PLK1-PBD and PLK4-PB3: structure-guided pharmacophore modelling, virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation.

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Changhao Zhao, Hanying Wu, Huajing Liu, Hui Dong, Miao-Miao Niu, Kun Shi, Fengzhen Wang
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引用次数: 0

Abstract

Aberrant expression of PLK1 and PLK4 is closely associated with tumourigenesis, and their simultaneous inhibition can effectively suppress tumour proliferation. In this study, we successfully identified peptide inhibitors (Peptides 1-5) capable of simultaneously targeting PLK1-PBD and PLK4-PB3 via pharmacophore-based virtual screening. Binding affinity analyses demonstrated that all candidate peptides exhibited nanomolar binding affinity for both targets. In vitro cancer cell growth inhibition assays revealed that these peptides could suppress the growth of cervical cancer cells. Among them, Peptide-2 showed the optimal binding affinity and anticancer cell proliferative activity (PLK1-PBD: Kd = 8.02 ± 0.16 nM; PLK4-PB3: Kd = 11.32 ± 0.19 nM; IC50 = 0.44 ± 0.03). Molecular dynamics (MD) simulations further predicted that Peptide-2 could stably bind to the binding sites of both PLK1-PBD and PLK4-PB3. This study reported a novel peptide inhibitor Peptide-2 with potent dual-target inhibitory activity against PLK1-PBD/PLK4-PB3, providing a novel strategy for cancer therapy.

新型PLK1-PBD和PLK4-PB3双靶向抑制剂的发现:结构引导药效团建模、虚拟筛选、分子对接、分子动力学模拟和生物学评价。
PLK1和PLK4的异常表达与肿瘤的发生密切相关,同时抑制它们可以有效抑制肿瘤的增殖。在这项研究中,我们通过基于药物团的虚拟筛选成功地鉴定了能够同时靶向PLK1-PBD和PLK4-PB3的肽抑制剂(肽1-5)。结合亲和力分析表明,所有候选肽对两个靶点都具有纳米级的结合亲和力。体外癌细胞生长抑制实验表明,这些肽能抑制宫颈癌细胞的生长。其中,Peptide-2表现出最佳的结合亲和力和抗肿瘤细胞增殖活性(PLK1-PBD: Kd = 8.02±0.16 nM;PLK4-PB3: Kd = 11.32±0.19 nM;Ic50 = 0.44±0.03)。分子动力学(MD)模拟进一步预测了Peptide-2可以稳定结合PLK1-PBD和PLK4-PB3的结合位点。本研究报道了一种新的肽抑制剂peptide -2,对PLK1-PBD/PLK4-PB3具有有效的双靶点抑制活性,为癌症治疗提供了一种新的策略。
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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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