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Updated: Oct 8, 2025
Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
Artificial intelligence-based identification of octenidine as a Bcl-xL inhibitor
Anh Thi Ngoc Bui1, Hyojin Son2, Seulki Park1
1Disease Target Structure Research Center, KRIBB, Daejeon, 31441, Republic of Korea.
Abstract:
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.
Insights
Octenidine is identified as a novel inhibitor of the anti-apoptotic protein Bcl-xL. This discovery offers a new strategy for triggering apoptosis in cancer cells, potentially advancing anticancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Apoptosis is crucial for cellular balance and cancer prevention.
- Bcl-xL, an anti-apoptotic protein, is a key regulator of mitochondrial apoptosis and a target for cancer treatment.
Purpose of the Study:
- To identify novel Bcl-xL inhibitors from approved drugs.
- To elucidate the mechanism of octenidine's interaction with Bcl-xL and its anticancer effects.
Main Methods:
- Structural feature-based deep learning and molecular docking were used to screen for Bcl-xL inhibitors.
- Nuclear Magnetic Resonance (NMR) spectroscopy and NanoBiT protein-protein interaction assays were employed to study binding and inhibition.
- Cell proliferation assays were conducted on MCF-7 breast and H1299 lung cancer cell lines.
Main Results:
- Octenidine was identified as a novel Bcl-xL inhibitor.
- NMR confirmed octenidine binds to the BH3 domain-binding hydrophobic region of Bcl-xL.
- Octenidine inhibited Bcl-xL/Bak-BH3 interaction and promoted apoptosis, reducing cancer cell proliferation.
Conclusions:
- Octenidine directly targets anti-apoptotic Bcl-xL.
- Octenidine triggers mitochondrial apoptosis in cancer cells, presenting a potential new anticancer therapeutic strategy.
