Second coordination sphere regulates nanozyme inhibition to assist early drug discovery

Yu Wu, Jian Li, Wenxuan Jiang, Weiqing Xu, Lirong Zheng, Canglong Wang, Wenling Gu and Chengzhou Zhu ()
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Yu Wu: Central China Normal University
Jian Li: Central China Normal University
Wenxuan Jiang: Central China Normal University
Weiqing Xu: Central China Normal University
Lirong Zheng: Chinese Academy of Science
Canglong Wang: Chinese Academy of Science
Wenling Gu: Central China Normal University
Chengzhou Zhu: Central China Normal University

Nature Communications, 2025, vol. 16, issue 1, 1-9

Abstract: Abstract Early drug discovery is a time- and cost-consuming task requiring enzymes. Although nanozymes with metal sites akin to metallocofactors display similar activities, the lack of proximal amino acids hinders them from more adequately mimicking enzymes for drug discovery purposes. Hence, the rational design of the nanozyme second coordination sphere is desirable yet remains challenging. Herein, we report a nanozyme featuring atomically dispersed Cu-N4 sites with proximal hydroxyl groups (CuNC-OH). Experimental and theoretical results reveal that Cu-N4 site and hydroxyl respectively behave as cofactor and amino acid of the enzymatic pocket to interact with adsorbates, regulating nanozyme activity and inhibition. This mechanism involving dual sites is similar to that of thyroid peroxidases, which enables specific inhibition of CuNC-OH by antithyroid drugs. Based on these findings, a nanozyme-assisted drug discovery kit is established to analyze inhibition features of thyroid peroxidase inhibitors and screen out promising antithyroid drugs with a significant cost reduction compared with traditional enzyme kits.

Date: 2025
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DOI: 10.1038/s41467-025-58291-7

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