Theoretical studies on the selectivity mechanisms of PI3Kδ inhibition with marketed idelalisib and its derivatives by 3D-QSAR, molecular docking, and molecular dynamics simulation

  • Jingyu ZhuEmail author
  • Ke Ke
  • Lei Xu
  • Jian JinEmail author
Original Paper


Phosphoinositide 3-kinases (PI3Ks) are crucial for cell proliferation, metabolism, motility, and cancer progression. Since the selective PI3Kδ inhibitor, idelalisib, was firstly approved by the FDA in 2014, large numbers of selective PI3Kδ inhibitors have been reported, but the detailed mechanisms of selective inhibition to PI3Kδ for idelalisib or its derivatives have not been well addressed. In this study, 3D-QSAR with COMFA, molecular docking, and molecular dynamic (MD) simulations was used to explore the binding modes between PI3Kδ and idelalisib derivatives. Firstly, a reliable COMFA model (q2 = 0.59, ONC = 8, r2 = 0.966) was built and the contour maps showed that the electrostatic field had more significant contribution to the bioactivities of inhibitors. Secondly, two molecular docking methods including rigid receptor docking (RRD) and induced fit docking (IFD) were employed to predict the docking poses of all the studied inhibitors and revealed the selective binding mechanisms. And then, the results of the MD simulation and the binding free energy decomposition verified that the binding of PI3Kδ/inhibitors was mainly contributed from hydrogen bonding and hydrophobic interactions and some key residues for selective binding were highlighted. Finally, based on the models developed, 14 novel inhibitors were optimized and some showed satisfactory predicted bioactivity. Taken together, the results provided by this study may facilitate the rational design of novel and selective PI3Kδ inhibitors.

Graphical abstract



PI3Kδ inhibitors Idelalisib 3D-QSAR COMFA Molecular docking Molecular dynamics simulations 


Funding information

The study was financially supported by the National Natural Science Foundation of China (No. 21807049, 81803430) and the Fundamental Research Funds for the Central Universities (JUSRP11892).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

894_2019_4129_MOESM1_ESM.docx (2.3 mb)
ESM 1 (DOCX 2327 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Pharmaceutical SciencesJiangnan UniversityWuxiChina
  2. 2.Institute of Bioinformatics and Medical Engineering, School of Electrical and Information EngineeringJiangsu University of TechnologyChangzhouChina

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