Artificial intelligence-based identification of octenidine as a Bcl-xL inhibitor

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Apoptosis plays an essential role in maintaining cellular homeostasis and preventing cancer progression. Bcl-xL, an anti-apoptotic protein, is an important modulator of the mitochondrial apoptosis pathway and is a promising target for anticancer therapy. In this study, we identified octenidine as a novel Bcl-xL inhibitor through structural feature-based deep learning and molecular docking from a library of approved drugs. The NMR experiments demonstrated that octenidine binds to the Bcl-2 homology 3 (BH3) domain-binding hydrophobic region that consists of the BH1, BH2, and BH3 domains in Bcl-xL. A structural model of the Bcl-xL/octenidine complex revealed that octenidine binds to Bcl-xL in a similar manner to that of the well-known Bcl-2 family protein antagonist ABT-737. Using the NanoBiT protein–protein interaction system, we confirmed that the interaction between Bcl-xL and Bak-BH3 domains within cells was inhibited by octenidine. Furthermore, octenidine inhibited the proliferation of MCF-7 breast and H1299 lung cancer cells by promoting apoptosis. Taken together, our results shed light on a novel mechanism in which octenidine directly targets anti-apoptotic Bcl-xL to trigger mitochondrial apoptosis in cancer cells.
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Issue Date
2022-01
Language
English
Article Type
Article
Citation

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.588, pp.97 - 103

ISSN
0006-291X
DOI
10.1016/j.bbrc.2021.12.061
URI
http://hdl.handle.net/10203/290956
Appears in Collection
BiS-Journal Papers(저널논문)
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