A Multiscale Simulation Approach to Modeling Drug-Protein Binding Kinetics
A Multiscale Simulation Approach to Modeling Drug-Protein Binding Kinetics
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DOI：
10.1021/acs.jctc.8b00687
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发表时间：
2018-11-01
影响因子：
5.5
通讯作者：
Gervasio, Francesco Luigi
中科院分区：
文献类型：
--
作者：
Haldar, Susanta;Comitani, Federico;Gervasio, Francesco Luigi
药物-靶点结合动力学最近已成为体内疗效和毒性的关键决定因素。然而，对其进行合理的优化以提高药效或减少药物的副作用是极其困难的。分子模拟可以在识别影响结合动力学的小配体及其蛋白质靶标的特征和性质方面发挥关键作用，但重大挑战包括(非)结合事件涉及的长时间尺度以及经验原子力场的有限准确性(例如，缺乏电子极化的变化)。为了克服这些障碍，我们提出了一种方法，将最先进的增强采样模拟和量子力学/分子力学(QM/MM)计算结合在BLYP/VDZ水平上，计算缔合自由能分布，并根据过渡态系综的结构和动力学来表征结合动力学。我们测试了我们的联合方法，将抗癌药物Imatinib与Src激酶结合，这是一种具有良好特征的癌症治疗靶点，具有复杂的结合机制，涉及显著的构象变化。结果表明，沿着结合路径的极化发生了显著的变化，这影响了预测的结合动力学。这很可能在配体与蛋白质靶标的结合中具有广泛的重要性。
Drug-target binding kinetics has recently emerged as a sometimes critical determinant of in vivo efficacy and toxicity. Its rational optimization to improve potency or reduce side effects of drugs is, however, extremely difficult. Molecular simulations can play a crucial role in identifying features and properties of small ligands and their protein targets affecting the binding kinetics, but significant challenges include the long time scales involved in (un)binding events and the limited accuracy of empirical atomistic force fields (lacking, e.g., changes in electronic polarization). In an effort to overcome these hurdles, we propose a method that combines state-of-the-art enhanced sampling simulations and quantum mechanics/molecular mechanics (QM/MM) calculations at the BLYP/VDZ level to compute association free energy profiles and characterize the binding kinetics in terms of structure and dynamics of the transition state ensemble. We test our combined approach on the binding of the anticancer drug Imatinib to Src kinase, a well-characterized target for cancer therapy with a complex binding mechanism involving significant conformational changes. The results indicate significant changes in polarization along the binding pathways, which affect the predicted binding kinetics. This is likely to be of widespread importance in binding of ligands to protein targets.