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Identification of PRMT5 inhibitors with novel scaffold structures through virtual screening and biological evaluations

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Abstract

Protein arginine methyltransferase 5 (PRMT5), an important member in PRMT family, has been validated as a promising anticancer target. In this study, through the combination of virtual screening and biological experiments, we have identified two PRMT5 inhibitors with novel scaffold structures. Among them, compound Y2431 showed moderate activity with IC50 value of 10.09 μM and displayed good selectivity against other methyltransferases. The molecular docking analysis and molecular dynamics (MD) simulations suggested that the compound occupied the substrate-arginine binding site. Furthermore, Y2431 exhibited anti-proliferative activity to leukemia cells by inducing cell cycle arrest. Overall, the hit compound could provide a novel scaffold for further optimization of small-molecule PRMT5 inhibitors.

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Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by National Natural Science Foundation of China (81803339 to J.J.) and Jiaxing Science and Technology Project (2018AY32002 to C.C.).

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Author notes

  1. Qian Zhang and Lun Zhang contributed equally to this work.

Authors and Affiliations

  1. College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China

    Qian Zhang, Lun Zhang, Jia Jin, Haofeng Hu, Xiaoqing Ye, Lei Wang & Fei Ye

  2. Department of Surgery, The Second Affiliated Hospital of Jia Xing University, Jiaxing, China

    Yaohua Fan, Xiaoguang Wang & Chenxi Cao

  3. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materta Medica, Chinese Academy of Sciences, Shanghai, China

    Xiaoqing Ye

Authors
  1. Qian Zhang
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  2. Lun Zhang
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  3. Jia Jin
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  5. Xiaoguang Wang
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  8. Lei Wang
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  9. Chenxi Cao
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  10. Fei Ye
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Contributions

All authors contributed to the study conception and design. Project design, manuscript editing were performed by Fei Ye. Material preparation, data collections, and results analysis were performed by Qian Zhang, Lun Zhang, Jia Jin, Chenxi Cao, Yaohua Fan, Xiaoguang Wang, Haofeng Hu and Xiaoqing Ye.

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Correspondence to Chenxi Cao or Fei Ye.

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Zhang, Q., Zhang, L., Jin, J. et al. Identification of PRMT5 inhibitors with novel scaffold structures through virtual screening and biological evaluations. J Mol Model 28, 184 (2022). https://doi.org/10.1007/s00894-022-05125-8

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