期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 588, 期 -, 页码 97-103出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2021.12.061
关键词
Bcl-xL; Arti ficial intelligence-based screening; Octenidine; Anti-cancer effect; NMR spectroscopy
资金
- National Research Foundation - Korean government (MSIT) [NRF-2017R1E1A1A01074403, NRF-2019M3E5D4069903, NRF-2019M3A9C4076156, NRF-2019M3E5D4069644]
- KRIBB Research Initiative Program [KGM9952112]
In this study, octenidine was identified as a novel Bcl-xL inhibitor through structural feature-based deep learning and molecular docking. By targeting the anti-apoptotic protein Bcl-xL, octenidine promotes apoptosis in cancer cells, inhibiting their proliferation.
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. (c) 2021 Elsevier Inc. All rights reserved.
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