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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Discovery of a Novel Small-molecule Interleukin-6 Inhibitor Through Virtual Screening Using Artificial Intelligence

Author(s): Yoshiaki Sato, Ikuo Kashiwakura*, Masaru Yamaguchi, Hironori Yoshino, Takeshi Tanaka, Ken Ikeda, Zhengmao Ye, Hirotsugu Komatsu, Takao Matsuzaki and Masato Hosoda

Volume 18, Issue 6, 2022

Published on: 11 January, 2022

Page: [694 - 700] Pages: 7

DOI: 10.2174/1573406418666211116144243

Price: $65

Abstract

Background: Interleukin-6 (IL-6) is a multifunctional cytokine involved in various cell functions and diseases. Thus far, several IL-6 inhibitors, such as humanized monoclonal antibody have been used to block excessive IL-6 signaling causing autoimmune and inflammatory diseases. However, anti-IL-6 and anti-IL-6 receptor monoclonal antibodies have some clinical disadvantages, such as a high cost, unfavorable injection route, and tendency to mask infectious diseases. While a small-molecule IL-6 inhibitor would help mitigate these issues, none are currently available.

Objective: The present study evaluated the biological activities of identified compounds on IL-6 stimulus.

Methods: We virtually screened potential IL-6 binders from a compound library using INTerprotein’s Engine for New Drug Design (INTENDD®) followed by the identification of more potent IL-6 binders with artificial intelligence (AI)-guided INTENDD®. The biological activities of the identified compounds were assessed with the IL-6-dependent cell line 7TD1.

Results: The compounds showed the suppression of IL-6-dependent cell growth in a dose-dependent manner. Furthermore, the identified compound inhibited expression of IL-6-induced phosphorylation of signal transducer and activator of transcription 3 in a dose-dependent manner.

Conclusion: Our screening compound demonstrated an inhibitory effect on IL-6 stimulus. These findings may serve as a basis for the further development of small-molecule IL-6 inhibitors.

Keywords: Artificial intelligence, virtual screening, small molecule inhibitor, interleukin-6, protein-protein interactions, signal transducer and activator of transcription 3.

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