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Identification of novel EED-EZH2 PPI inhibitors using an in silico fragment mapping method

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Abstract

Enhancer of zeste homolog 2 (EZH2) is a histone lysine methyltransferase that is overexpressed in many cancers. Numerous EZH2 inhibitors have been developed as anticancer agents, but recent studies have also focused on protein–protein interaction (PPI) between embryonic ectoderm development (EED) and EZH2 as a novel drug discovery target. Because EED indirectly enhances EZH2 enzymatic activity, EED-EZH2 PPI inhibitors suppress the methyltransferase activity and inhibit cancer growth. By contrast to the numerous promising EZH2 inhibitors, there are a paucity of EED-EZH2 PPI inhibitors reported in the literature. Here, we aimed to discover novel EED-EZH2 PPI inhibitors by first identifying possible binders of EED using an in-house knowledge-based in silico fragment mapping method. Next, 3D pharmacophore models were constructed from the arrangement pattern of the potential binders mapped onto the EED surface. In all, 16 compounds were selected by 3D pharmacophore-based virtual screening followed by docking-based virtual screening. In vitro evaluation revealed that five of these compounds exhibited inhibitory activities. This study has provided structural insights into the discovery and the molecular design of novel EED-EZH2 PPI inhibitors using an in silico fragment mapping method.

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Code availability

Fsubsite is freely available for academic use upon request.

Data availability

The datasets generated or analyzed during this study are available from the corresponding author upon request.

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  1. Kensuke Misawa

    Present address: Biological Science Laboratories, Kao Corporation, 2606 Akabane, Ichikai-machi, Haga-gun, Tochigi, 321-3497, Japan

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan

    Kensuke Misawa, Noriyuki Yamaotsu & Shuichi Hirono

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Contributions

Kensuke Misawa and Shuichi Hirono designed the study. Kensuke Misawa performed the computations, analyzed the data, and wrote the initial draft of the manuscript. Noriyuki Yamaotsu contributed to the development of the methods and interpretation of the data. All authors approved the final version of the manuscript and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.

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Correspondence to Kensuke Misawa or Shuichi Hirono.

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Misawa, K., Yamaotsu, N. & Hirono, S. Identification of novel EED-EZH2 PPI inhibitors using an in silico fragment mapping method. J Comput Aided Mol Des 35, 601–611 (2021). https://doi.org/10.1007/s10822-021-00378-6

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