Elucidating the Selective Mechanism of Drugs Targeting Cyclin-Dependent Kinases with Integrated MetaD-US Simulation,Journal of Chemical Information and Modeling

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Elucidating the Selective Mechanism of Drugs Targeting Cyclin-Dependent Kinases with Integrated MetaD-US Simulation
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2024-08-22 , DOI: 10.1021/acs.jcim.4c01196
Lingling Wang _{1,

2} , Shu Li ₁ , Sutong Xiang ₂ , Huanxiang Liu ₁ , Huiyong Sun ₂

Affiliation

Cyclin-dependent kinases (CDKs), including CDK12 and CDK13, play crucial roles in regulating the cell cycle and RNA polymerase II activity, making them vital targets for cancer therapies. SR4835 is a selective inhibitor of CDK12/13, showing significant potential for treating triple-negative breast cancer. To elucidate the selective mechanism of SR4835 among three CDKs (CDK13/12/9), we developed an innovative enhanced sampling method, integrated well-tempered metadynamics-umbrella sampling (IMUS). IMUS synergistically combines the comprehensive pathway exploration capability of well-tempered metadynamics (WT-MetaD) with the precise free energy calculation capability of umbrella sampling, enabling the efficient and accurate characterization of drug-target interactions. The accurate calculation of binding free energy and the detailed analysis of the kinetic mechanism of the drug-target interaction using IMUS successfully elucidate the drug selectivity mechanism targeting the three CDKs, showing that the selectivity is primarily arising from differences in the stability of H-bonds within the Hinge region of the kinases and the interaction patterns during the protein–ligand recognition process. These findings also underscore the utility of IMUS in efficiently and accurately capturing drug-target interaction processes with clear mechanisms.

中文翻译：

通过集成 MetaD-US 模拟阐明针对周期蛋白依赖性激酶的药物的选择性机制

细胞周期蛋白依赖性激酶 (CDK)，包括 CDK12 和 CDK13，在调节细胞周期和 RNA 聚合酶 II 活性方面发挥着至关重要的作用，使其成为癌症治疗的重要靶点。 SR4835 是一种选择性 CDK12/13 抑制剂，显示出治疗三阴性乳腺癌的巨大潜力。为了阐明 SR4835 在三个 CDK（CDK13/12/9）中的选择性机制，我们开发了一种创新的增强采样方法，集成良好的元动力学-伞采样（IMUS）。 IMUS将良好的元动力学（WT-MetaD）的全面路径探索能力与伞式采样的精确自由能计算能力相结合，能够高效、准确地表征药物-靶标相互作用。利用IMUS精确计算结合自由能并详细分析药物与靶标相互作用的动力学机制，成功阐明了针对三种CDK的药物选择性机制，表明选择性主要源于氢键稳定性的差异激酶的铰链区域内以及蛋白质-配体识别过程中的相互作用模式。这些发现还强调了 IMUS 在有效、准确地捕获具有明确机制的药物-靶标相互作用过程方面的效用。

更新日期：2024-08-22

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