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Computational study reveals substituted benzimidazole derivatives’ binding selectivity to PI3Kδ and PI3Kγ

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Abstract

Phosphatidylinositol 3-kinase (PI3K) is a key regulatory kinase in the PI3K/AKT/mTOR signaling pathway, which is involved in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. Class IA PI3K isoforms γ and δ share a highly homologous ATP binding site and are distinguished by only a few residues around the binding site. Subtype-selective inhibitors have been proven to have great advantages in tumor treatment. Preliminary studies have obtained PI3K inhibitors bearing a benzimidazole structural motif with a certain selectivity for PI3Kδ and PI3Kγ subtypes. On this basis, we investigated the selective inhibitory mechanism of PI3Kδ and PI3Kγ using four developed inhibitors via molecular docking, molecular dynamics, binding free energy calculations, and residue energy decomposition. This study could provide references for the further development of PI3K-isoform-selective inhibitors.

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Data Availability

All the data and material can be easily assessed in manuscript and supporting information (SI).

Code availability

SYBYL-X (2.0, own copyright), LigPlus (V.2.2.4, open source), AutoDockTools (V.1.5.6, open source), AutoDock Vina program (V.1.1.2, open source), AMBER 16 (own copyright), and PyMOL (V.2.1.1,open source).

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Funding

This work was financially supported by the National Natural Science Foundation of China (82,060,625), the Guizhou Provincial Natural Science Foundation ([2020]1Z073), the National Science Foundation of Health and Family planning Commission of Guizhou Province (gzwjkj2019-1–178), and the Young crop project of Guizhou Medical University (19NSP073).

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Author notes

  1. Na-Na Zhang and Xue Bai These authors contributed equally to this work

Authors and Affiliations

  1. State Key Laboratory of Functions and Applications of Medicinal Plants, College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550025, China

    Na-Na Zhang, Shan-Shan Zhao, Xue-Mei Zheng, Lei Tang, Sheng-Gang Yang & Ji-Quan Zhang

  2. Pharmacy Department of Guizhou Provincial People’s Hospital, Guiyang, 55000, China

    Xue Bai

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  1. Na-Na Zhang
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Contributions

The computational work was performed by Na-Na Zhang, Shan-Shan Zhao, and Xue-Mei Zheng; data analysis was conducted by Xue Bai, Lei Tang, Sheng-Gang Yang, and Ji-Quan Zhang; and the manuscript was written by Na-Na Zhang and revised by Ji-Quan Zhang.

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Correspondence to Sheng-Gang Yang or Ji-Quan Zhang.

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Zhang, NN., Bai, X., Zhao, SS. et al. Computational study reveals substituted benzimidazole derivatives’ binding selectivity to PI3Kδ and PI3Kγ. J Mol Model 28, 123 (2022). https://doi.org/10.1007/s00894-022-05096-w

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