Targeting mitochondrial dynamics: an in-silico approach for repurposing antifungal drugs in OSCC treatment

• Published in: Journal of biomolecular structure & dynamics 2024-11, p.1-14
• Main Authors: Raali, Rohith, Sivakumar, Neha, Vardhan J, Harsh, P K, Suresh
• Format: Article
• Language: English
• ISSN: 0739-1102; 1538-0254; 1538-0254
• DOI: 10.1080/07391102.2024.2425831

Drug repurposing for cancer treatment is a valuable strategy to identify existing drugs with known safety profiles that could combat the neoplasm, by reducing costs. Oral squamous cell carcinoma, an ulcer-proliferative lesion on the mucosal epithelium, is the most common oral malignancy. About 10% of cancer patients within the Indian subcontinent suffer from OSCC, primarily due to chewing of betel plant derivatives. Concomitant administration of the chemotherapeutic agent (Cisplatin/Paclitaxel) is the treatment of choice. Analysis of the oral mycobiome of OSCC patients has projected the role of Candida albicans in potentiating OSCC. Hence, repurposing antifungal drugs emerges as a promising approach, as these drugs could target both the cancer cells and the infection. Cancer cells often have heightened energy requirements, and targeting mitochondrial proteins to disrupt mitochondrial division and induce dysfunction contributing to cell death, offers a method for treating OSCC. We identified 18 mitochondrial targets playing a crucial role in the maintenance of mitochondrial homeostasis. They were docked against 125 antifungal ligand molecules sourced from PUBCHEM. Ligand profiling was performed using Lipinski's rule of 5, SwissADME and ProTox. Also, molecular dynamics and MM-PBSA were performed to validate our results. Among all protein ligand interactions, we observed that targeting DRP1 with itraconazole yielded superior binding and stability. Overall, lower toxicity and thumping ADME properties solidified the choice of ligand. We hope this experimental approach will enable us to provide a basis for selecting a lead molecule for a possible novel nano-formulation and validate our finding through in-vitro cell line-based testing.