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Archiv der Pharmazie. 2025 Apr;358(4):e3126. doi: 10.1002/ardp.202500102 Q24.32024

Ternary Complex Modeling, Induced Fit Docking and Molecular Dynamics Simulations as a Successful Approach for the Design of VHL-Mediated PROTACs Targeting the Kinase FLT3

三元复合物建模、诱导拟合对接和分子动力学模拟作为成功设计基于VHL的FLT3蛋白降解PROTACs的方法 翻译改进

Husam Nassar  1, Anne-Christin Sarnow  1, Ismail Celik  1  2, Mohamed Abdelsalam  1  3, Dina Robaa  1, Wolfgang Sippl  1

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作者单位

  • 1 Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany.
  • 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
  • DOI: 10.1002/ardp.202500102 PMID: 40223615

    摘要 中英对照阅读

    Proteolysis targeting chimeras (PROTACs) have proven to be a novel approach for the degradation of disease-causing proteins in drug discovery. One of the E3 ligases for which efficient PROTACs have been described is the Von Hippel-Lindau factor (VHL). However, the development of PROTACs has so far often relied on a minimum of computational tools, so that it is mostly based on a trial-and-error process. Therefore, there is a great need for resource- and time-efficient structure-based or computational approaches to streamline PROTAC design. In this study, we present a combined computational approach that integrates static ternary complex formation, induced-fit docking, and molecular dynamics (MD) simulations. Our methodology was tested using four experimentally derived ternary complex structures of VHL PROTACs, reported for BRD4, SMARCA2, FAK, and WEE1. In addition, we applied the validated approach to model a recently in-house developed FLT3-targeted PROTAC (MA49). The results show that static ternary models generated with a protein-protein docking method implemented in the software MOE have a high predictive power for reproducing the experimental 3D structures. The induced-fit docking of different active PROTACs to their respective models showed the reliability of this model for the development of new VHL-mediated degraders. In particular, the induced-fit docking was sensitive to structural changes in the PROTACs, as evidenced by the failed binding modes of the PROTAC negative controls. Furthermore, MD simulations confirmed the stability of the generated complexes and emphasized the importance of dynamic studies for understanding the relationship between PROTAC structure and function.

    Keywords: FLT3; MD simulation; PROTACs; VHL; induced‐fit docking.

    Keywords:ternary complex modeling; induced fit docking; molecular dynamics simulations; vhl-mediated protacs; kinase flt3

    蛋白酶靶向嵌合体(PROTACs)已被证明是药物发现中降解致病蛋白质的一种新型方法。用于高效PROTAC的E3连接酶之一就是冯·希佩尔-林道因子(VHL)。然而,迄今为止,PROTAC的发展通常依赖于最少的计算工具,因此主要是基于试错过程进行的。因此,迫切需要资源和时间高效的结构基础或计算方法来优化PROTAC的设计流程。在本研究中,我们提出了一种结合静态三元复合物形成、诱导契合对接和分子动力学(MD)模拟的综合计算方法。我们的方法通过四种实验上得到的VHL PROTACs三元复合物结构进行了测试,这些结构分别针对BRD4、SMARCA2、FAK和WEE1。此外,我们应用了经过验证的方法来建模最近内部开发的一种FLT3靶向PROTAC(MA49)。结果显示,使用MOE软件中实现的蛋白质-蛋白质对接方法生成的静态三元模型具有高度预测能力,能够再现实验三维结构。不同活性PROTACs对其相应模型进行诱导契合对接显示了该模型在新VHL介导降解剂开发中的可靠性。特别是,诱导契合对接对PROTACs的结构变化敏感,这一点通过负对照PROTAC结合模式失败得到了证实。此外,MD模拟确认了生成复合物的稳定性,并强调了动态研究对于理解PROTAC构效关系的重要性。

    关键词: FLT3;MD模拟;PROTACs;VHL;诱导契合对接。

    关键词:三元复合物建模; 诱导契合对接; 分子动力学模拟; VHL介导的PROTACs; 激酶FLT3

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    期刊名:Archiv der pharmazie

    缩写:ARCH PHARM

    ISSN:0365-6233

    e-ISSN:1521-4184

    IF/分区:4.3/Q2

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    Ternary Complex Modeling, Induced Fit Docking and Molecular Dynamics Simulations as a Successful Approach for the Design of VHL-Mediated PROTACs Targeting the Kinase FLT3