Molecular modeling strategy for detailing the primary mechanism of action of copanlisib to PI3K: combined ligand-based and target-based approach.
Molecular modeling strategy for detailing the primary mechanism of action of copanlisib to PI3K: combined ligand-based and target-based approach.
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DOI：
10.1080/07391102.2023.2246569
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发表时间：
2023-08
影响因子：
4.4
通讯作者：
Jingyu Zhu;Xintong Li;Huiqin Meng;Lei Jia;Lei Xu;Yanfei Cai;Yun Chen;Jian Jin;Li Yu
中科院分区：
文献类型：
--
作者：
Jingyu Zhu;Xintong Li;Huiqin Meng;Lei Jia;Lei Xu;Yanfei Cai;Yun Chen;Jian Jin;Li Yu
由于磷脂酰肌醇3-激酶（PI 3 K）信号通路的失调与癌症、炎症和自身免疫的发病机制相关，因此PI 3 K已成为药物开发的有吸引力的靶点。尽管copanlisib是第一个被批准用于临床的pan-PI 3 K抑制剂，但其作用于PI 3 K的确切机制尚未完全阐明。为了揭示PI 3 K和copanlisib之间的结合机制和构效关系，利用结合三维定量构效关系（3D-QSAR）、药效团模型和分子动力学（MD）模拟的综合建模方法。首先，copanlisib及其衍生物的构效关系进行了探索，通过构建一个3D-QSAR。然后，通过建立共同特征药效团模型，确定关键化学特征。最后，进行MD模拟以阐明copanlisib与不同PI 3 K亚型之间的重要相互作用，并突出紧密结合抑制剂的关键残基。本研究在理论水平上揭示了copanlisib对PI 3 K作用的主要机制，这些发现可能为合理设计pan-PI 3 K抑制剂提供指导。Sarma
Since dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is associated with the pathogenesis of cancer, inflammation, and autoimmunity, PI3K has emerged as an attractive target for drug development. Although copanlisib is the first pan-PI3K inhibitor to be approved for clinical use, the precise mechanism by which it acts on PI3K has not been fully elucidated. To reveal the binding mechanisms and structure-activity relationship between PI3K and copanlisib, a comprehensive modeling approach that combines 3D-quantitative structure-activity relationship (3D-QSAR), pharmacophore model, and molecular dynamics (MD) simulation was utilized. Initially, the structure-activity relationship of copanlisib and its derivatives were explored by constructing a 3D-QSAR. Then, the key chemical characteristics were identified by building common feature pharmacophore models. Finally, MD simulations were performed to elucidate the important interactions between copanlisib and different PI3K subtypes, and highlight the key residues for tight-binding inhibitors. The present study uncovered the principal mechanism of copanlisib's action on PI3K at the theoretical level, and these findings might provide guidance for the rational design of pan-PI3K inhibitors.Communicated by Ramaswamy H. Sarma.