In silico screening of natural products as uPAR inhibitors via multiple structure-based docking and molecular dynamics simulations.

IF 2.7 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Biomolecular Structure & Dynamics Pub Date : 2025-04-01 Epub Date: 2023-12-18 DOI:10.1080/07391102.2023.2295386
Song Xie, Guiqian Yang, Juhong Wu, Longguang Jiang, Cai Yuan, Peng Xu, Mingdong Huang, Yichang Liu, Jinyu Li
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Abstract

Cancer remains one of the most pressing challenges to global healthcare, exerting a significant impact on patient life expectancy. Cancer metastasis is a critical determinant of the lethality and treatment resistance of cancer. The urokinase-type plasminogen activator receptor (uPAR) shows great potential as a target for anticancer and antimetastatic therapies. In this work, we aimed to identify potential uPAR inhibitors by structural dynamics-based virtual screenings against a natural product library on four representative apo-uPAR structural models recently derived from long-timescale molecular dynamics (MD) simulations. Fifteen potential inhibitors (NP1-NP15) were initially identified through molecular docking, consensus scoring, and visual inspection. Subsequently, we employed MD-based molecular mechanics-generalized Born surface area (MM-GBSA) calculations to evaluate their binding affinities to uPAR. Structural dynamics analyses further indicated that all of the top 6 compounds exhibited stable binding to uPAR and interacted with the critical residues in the binding interface between uPAR and its endogenous ligand uPA, suggesting their potential as uPAR inhibitors by interrupting the uPAR-uPA interaction. We finally predicted the ADMET properties of these compounds. The natural products NP5, NP12, and NP14 with better binding affinities to uPAR than the uPAR inhibitors previously discovered by us were proven to be potentially orally active in humans. This work offers potential uPAR inhibitors that may contribute to the development of novel effective anticancer and antimetastatic therapeutics.

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通过多种基于结构的对接和分子动力学模拟,对作为 uPAR 抑制剂的天然产物进行硅学筛选。
癌症仍然是全球医疗保健面临的最紧迫挑战之一,对患者的预期寿命产生重大影响。癌症转移是决定癌症致死率和耐药性的关键因素。尿激酶型纤溶酶原激活物受体(uPAR)作为抗癌和抗转移疗法的靶点显示出巨大的潜力。在这项工作中,我们的目标是通过基于结构动力学的虚拟筛选,针对最近从长时间尺度分子动力学(MD)模拟中得到的四个具有代表性的apo-uPAR结构模型的天然产物库,找出潜在的uPAR抑制剂。通过分子对接、共识评分和目测,我们初步确定了 15 种潜在的抑制剂(NP1-NP15)。随后,我们采用基于 MD 的分子力学-广义伯恩表面积(MM-GBSA)计算来评估它们与 uPAR 的结合亲和力。结构动力学分析进一步表明,前 6 种化合物都与 uPAR 有稳定的结合,并与 uPAR 及其内源配体 uPA 结合界面上的关键残基发生了相互作用,这表明它们有可能通过打断 uPAR 与 uPA 的相互作用而成为 uPAR 抑制剂。最后,我们对这些化合物的 ADMET 特性进行了预测。与我们之前发现的uPAR抑制剂相比,天然产物NP5、NP12和NP14与uPAR的结合亲和力更强,被证明具有潜在的人体口服活性。这项工作提供了潜在的 uPAR 抑制剂,可能有助于开发新型有效的抗癌和抗转移疗法。
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来源期刊
Journal of Biomolecular Structure & Dynamics
Journal of Biomolecular Structure & Dynamics 生物-生化与分子生物学
CiteScore
8.90
自引率
9.10%
发文量
597
审稿时长
2 months
期刊介绍: The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.
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