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Targeting mitochondrial dynamics: an in-silico approach for repurposing antifungal drugs in OSCC treatment
Rohith Raali1, Neha Sivakumar1, Harsh Vardhan J1
1Department of Biotechnology, SBST, VIT, Vellore.
Abstract:
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.
Insights
Repurposing antifungal drugs like itraconazole shows promise for treating oral squamous cell carcinoma (OSCC). This approach targets cancer cell mitochondria and potential Candida albicans infections, offering a cost-effective strategy.
Area of Science:
- Oncology
- Pharmacology
- Mycology
Background:
- Oral squamous cell carcinoma (OSCC) is a prevalent malignancy, particularly in the Indian subcontinent, often linked to betel quid chewing.
- Current treatments involve chemotherapy (Cisplatin/Paclitaxel), but drug repurposing offers a cost-effective alternative with known safety profiles.
- The oral mycobiome, specifically Candida albicans, has been implicated in potentiating OSCC, suggesting antifungal drugs as a dual-action therapeutic strategy.
Purpose of the Study:
- To explore the potential of repurposing antifungal drugs for OSCC treatment by targeting mitochondrial dysfunction.
- To identify novel drug candidates by screening antifungal compounds against key mitochondrial targets in cancer cells.
Main Methods:
- Computational screening of 125 antifungal ligands against 18 identified mitochondrial targets crucial for OSCC cell homeostasis.
- In silico analysis including Lipinski's rule of 5, SwissADME, ProTox, molecular dynamics, and MM-PBSA to evaluate drug-likeness, toxicity, and binding stability.
- Identification of DRP1 as a key mitochondrial target and itraconazole as a lead repurposing candidate.
Main Results:
- Itraconazole demonstrated superior binding affinity and stability when targeting the DRP1 mitochondrial protein.
- The identified lead molecule, itraconazole, exhibited favorable ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) properties.
- The study validated a computational approach for identifying repurposed drugs against cancer-specific mitochondrial targets.
Conclusions:
- Repurposing itraconazole presents a promising therapeutic strategy for OSCC, potentially targeting both cancer cells and associated fungal infections.
- The findings provide a foundation for developing novel nano-formulations and subsequent in vitro validation for OSCC treatment.
- This study highlights the potential of targeting mitochondrial dynamics in cancer therapy through drug repurposing.
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