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Computational investigation of the selectivity mechanisms of PI3Kδ inhibition with marketed idelalisib: combined molecular dynamics simulation and free energy calculation

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Abstract

Phosphoinositide 3-kinase (PI3K) has been considered to be a potential drug target for the treatment of several human body diseases. Nowadays, great efforts have been made on the development of selective PI3Kδ inhibitors because of the FDA approval of idelalisib, which is the first listed PI3K inhibitor. But serious side effects occur during the use of idelalisib that greatly promotes the development of novel PI3Kδ inhibitors. Nevertheless, idelalisib is still an important milestone in the development of selective PI3Kδ inhibitors, but the detailed selective binding mechanisms between idelalisib and PI3Ks have not been well elucidated. Therefore, in this study, an integrated modeling strategy combining molecular docking, molecular dynamics simulation, and free energy calculation was performed to reveal the molecular-level binding mechanisms of idelalisib and class I PI3K. First, molecular docking was carried on to obtain a reasonable binding posture of idelalisib in different PI3K isoforms. Then, key residues for selective inhibition of PI3Kδ were highlighted by molecular dynamics simulation and energy calculations. Finally, idelalisib was also compared with its lead compound, IC87114, to reveal the reason for the higher potency of Idelalisib for PI3Kδ. We hope that this study would provide some guidance for the rational design of selective PI3Kδ inhibitors.

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Funding

The study was supported by the National Natural Science Foundation of China (No. 21807049), the Fundamental Research Funds of Changzhou Vocational Institute of Engineering (11130300117010), the Fundamental Research Funds for the Central Universities (JUSRP51703A), and the Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (PPZY2015B146).

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Authors and Affiliations

  1. School of Pharmaceutical Sciences, Jiangnan University, Wuxi, 214122, Jiangsu, China

    Jingyu Zhu, Haoer Zhang, Heyang Sun, Yun Chen, Yanfei Cai & Jian Jin

  2. School of Inspection and Testing Certification, Changzhou Vocational Institute of Engineering, Changzhou, 213164, China

    Li Yu

  3. School of Biotechnology, Jiangnan University, Wuxi, 214122, Jiangsu, China

    Huazhong Li

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  1. Jingyu Zhu
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Contributions

Z.J., L.H., and J.J. developed the study concept and design. Z.H. and S.H. performed the modeling studies. Z.H., Y.L., and C.Y. carried out the data analysis. Z.J., Z.H., and Y.L. drafted the manuscript, C.Y., L.H., and J.J. approved the manuscript.

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Correspondence to Jingyu Zhu or Jian Jin.

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Jingyu Zhu, Haoer Zhang and Li Yu are Equivalent authors

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Zhu, J., Zhang, H., Yu, L. et al. Computational investigation of the selectivity mechanisms of PI3Kδ inhibition with marketed idelalisib: combined molecular dynamics simulation and free energy calculation. Struct Chem 32, 699–707 (2021). https://doi.org/10.1007/s11224-020-01643-4

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