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Integrated molecular modeling techniques to reveal selective mechanisms of inhibitors to PI3Kδ with marketed Idelalisib
Author(s) -
Zhu Jingyu,
Jia Lei,
Jiang Yingmin,
Yu Qianqian,
Xu Lei,
Cai Yanfei,
Chen Yun,
Li Huazhong,
Gang Huang,
Liang Wenqing,
Jin Jian
Publication year - 2021
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13838
Subject(s) - idelalisib , pharmacophore , pi3k/akt/mtor pathway , computational biology , chemistry , quantitative structure–activity relationship , molecular dynamics , molecular model , computer science , biochemistry , stereochemistry , biology , signal transduction , computational chemistry , genetics , ibrutinib , chronic lymphocytic leukemia , leukemia
Phosphatidylinositol‐3‐kinase (PI3K) is important for cell proliferation, differentiation, and apoptosis, and the diverse physiological roles of different PI3K isoforms have highlighted the significance of the development of PI3Kδ inhibitors. A large number of PI3Kδ inhibitors have been reported after the FDA approval of Idelalisib, but the clinical use of Idelalisib was limited because of its serious side effects. Therefore, great efforts have been made on the development of PI3Kδ inhibitors with higher selectivity and lower toxicity, but there is no new PI3Kδ inhibitor coming into the market so far. Even so, as the first listed PI3K inhibitor, Idelalisib could be used as an effective tool to investigate the selective inhibition mechanism of PI3Kδ. Thus, in this study, a modeling strategy integrated 3D‐QSAR, pharmacophore model, and molecular dynamics simulation was employed to reveal the key chemical characteristics of Idelalisib analogs and the binding pattern between the inhibitors and PI3Kδ. First, the CoMFA model with high statistical significance was built to reveal the general structure–activity relationships. And then, a reliable pharmacophore model with a robust discrimination capability was constructed to expound the main chemical characteristics of the PI3Kδ inhibitors. Finally, molecular dynamics simulation was conducted to explore the binding modes and some key residues refer to δ‐selective binding were highlighted with binding‐free energy calculation. In summary, these models and results would provide some effective help for the discovery or the rational design of novel PI3Kδ inhibitors.