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

• Published in: Biochemical and biophysical research communications 2022-01, Vol.588, p.97-103
• Main Authors: Bui, Anh Thi Ngoc, Son, Hyojin, Park, Seulki, Oh, Sohee, Kim, Jin-Sik, Cho, Jin Hwa, Hwang, Hye-Jin, Kim, Jeong-Hoon, Yi, Gwan-Su, Chi, Seung-Wook
• Format: Article
• Language: English
• Subjects: Anti-cancer effect; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Artificial Intelligence; Artificial intelligence-based screening; bcl-2 Homologous Antagonist-Killer Protein - chemistry; bcl-2 Homologous Antagonist-Killer Protein - metabolism; bcl-X Protein - antagonists & inhibitors; bcl-X Protein - chemistry; Bcl-xL; Cell Line; Cell Proliferation - drug effects; Humans; Imines - chemistry; Imines - pharmacology; Molecular Docking Simulation; Neoplasms - pathology; NMR spectroscopy; Octenidine; Protein Binding - drug effects; Pyridines - chemistry; Pyridines - pharmacology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2021.12.061

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. •Artificial intelligence-based identification of a novel Bcl-xL inhibitor.•Octenidine directly binds to the BH3 domain-binding site in Bcl-xL.•Octenidine inhibits Bcl-xL/Bak interaction to induce apoptosis.•Octenidine inhibits the proliferation of breast and lung cancer cells.•A novel action mechanism of octenidine for cancer therapy.