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

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. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Anh Thi Ngoc Bui, Hyojin Son, Seulki Park, Sohee Oh, Jin-Sik Kim, Jin Hwa Cho, Hye-Jin Hwang, Jeong-Hoon Kim, Gwan-Su Yi, Seung-Wook Chi. Artificial intelligence-based identification of octenidine as a Bcl-xL inhibitor. Biochemical and biophysical research communications. 2022 Jan 15;588:97-103

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PMID: 34953212

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