Asghari, NarjesSaei, Ali KianCordani, MarcoNayeri, ZahraMoosavi, Mohammad Amin2024-12-022024-12-022024Asghari, N., Saei, A. K., Cordani, M., Nayeri, Z., & Moosavi, M. A. (2024). Drug repositioning identifies potential autophagy inhibitors for the LIR motif p62/SQSTM1 protein. Computational Biology and Chemistry, 113, 108235. https://doi.org/10.1016/j.compbiolchem.2024.1082351476-927110.1016/j.compbiolchem.2024.108235https://hdl.handle.net/20.500.14352/111265MA.M. is supported by international (project on drug repositioning for LC3-interacting region of autophagy protein p62/SQSTM1 in breast cancer) and national (No. 884) grant programs funded by the National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran. M.C. is supported by grant RYC2021–031003I funded by MICIU/AEI/10.13039/501100011033 and, by European Union NextGenerationEU/PRTR.Autophagy is a critical cellular process for degrading damaged organelles and proteins under stressful conditions and has casually been shown to contribute to tumor survival and drug resistance. Sequestosome-1 (SQSTM1/p62) is an autophagy receptor that interacts with its binding partners via the LC3-interacting region (LIR). The p62 protein has been a highly researched target for its critical role in selective autophagy. In this study, we aimed to identify FDA-approved drugs that bind to the LIR motif of p62 and inhibit its LIR function, which could be useful targets for modulating autophagy. To this, the homology model of the p62 protein was predicted using biological data, and docking analysis was performed using Molegro Virtual Docker and PyRx softwares. We further assessed the toxicity profile of the drugs using the ProTox-II server and performed dynamics simulations on the effective candidate drugs identified. The results revealed that the kanamycin, velpatasvir, verteporfin, and temoporfin significantly decreased the binding of LIR to the p62 protein. Finally, we experimentally confirmed that Kanamycin can inhibit autophagy-associated acidic vesicular formation in breast cancer MCF-7 and MDA-MB 231 cells. These repositioned drugs may represent novel autophagy modulators in clinical management, warranting further investigation.engjournal article1476-928Xhttps://doi.org/10.1016/j.compbiolchem.2024.108235https://www.sciencedirect.com/science/article/pii/S1476927124002238restricted access577.2616-006.04AutophagyP62/SQSTM1LIR motifDrug repurposingVirtual screeningMolecular dynamicBiología molecular (Biología)Oncología2415 Biología Molecular3201.01 Oncología