Drug repositioning identifies potential autophagy inhibitors for the LIR motif p62/SQSTM1 protein

• Published in: Computational biology and chemistry 2024-12, Vol.113, p.108235, Article 108235
• Main Authors: Asghari, Narjes, Saei, Ali Kian, Cordani, Marco, Nayeri, Zahra, Moosavi, Mohammad Amin
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Autophagy; Autophagy - drug effects; Cell Line, Tumor; Drug Repositioning; Drug repurposing; Humans; LIR motif; Molecular Docking Simulation; Molecular dynamic; P62/SQSTM1; Sequestosome-1 Protein - chemistry; Sequestosome-1 Protein - metabolism; Virtual screening
• ISSN: 1476-9271; 1476-928X; 1476-928X
• DOI: 10.1016/j.compbiolchem.2024.108235

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. [Display omitted] •Identified FDA-approved drugs inhibiting p62 LIR-autophagy interaction.•Kanamycin shown to reduce autophagy and viability in breast cancer cells.•Utilized computational docking to screen 2725 drugs for autophagy modulation.•Found specific drugs with potential for repositioning in cancer therapy.