In silico analysis for the screening and selection of repurposed drugs and mitochondrial targets for drug development and delivery for OSCC therapy

Title : In silico analysis for the screening and selection of repurposed drugs and mitochondrial targets for drug development and delivery for OSCC therapy

Abstract:

Globally, Oral Squamous Cell Cancer(OSCC) is a significant public health burden in terms of health care costs as well as lost man-hours and school-hours. This form of neoplasia ranks 3^rd both in terms of the number of cancers as well as in terms of the mortality data. Further, it is the most common form of cancer in males in India.¹ Despite variations in the statistics², the 5-year survival rate continues to be around 50%. One of the major determinants attributed to chemo and radio-resistance and relapse is the presence of cancer stem cells with alterations in bioenergetic features in these cells and changes in mitochondrial functions^3,4. In terms of mitochondrial dynamics, deregulation in their biogenesis (fusion and fission mechanisms) as well as mitophagy (removal of damaged mitochondria)-related processes are considered to be hallmark features of CSCs. Hence, since inhibition of mitophagy as well as mitochondrial biogenesis can possibly eradicate cancer stem cells by cell death mechanisms⁵, we identified key proteins involved in mitochondrial dynamics including mitophagy and apoptosis (based on an extensive literature search)⁶. Among the available OSCC anti-cancer drug treatment options, drug repurposing is considered to be a feasible, cost-effective and less time-consuming approach for developing efficacious and safe drugs targeting this human neoplastic condition⁷.

Since it is known than OSCC patients have opportunistic fungal infections, which can contribute to inflammation and oral neoplasia⁸, it was decided to screen anti-fungal drugs (125 ligands) using a combination of ligand profiling (PUBCHEM, Lipinsky’s rule of 5, SWISS-ADME and Pro-Tox3), molecular docking (AUTODOCK VINA, AUTODOCK). This in silico analysis was supplemented by performing MDS and MM-PBSA studies to further verify the natura of the binding over a 100 ns time period. Based on our defined in silico experimental flow, we observed that targeting DRP1 with itraconazole may possibly yield superior binding and stability, in comparison with our results obtained for all of the other ligand-target combinations⁶. While these results provide an opportunity to develop this molecule further (synthesis, characterization and in vitro cell line-based testing of a novel liposome-based nano-formulation), these positive findings have led us to extend our in-silico work by refining our findings as well as comparing these results with other categories of repurposed drugs specifically targeting our selected mitochondria-centric proteins⁹. Finally, keeping in mind the pivotal role played by mitochondria in terms of the therapeutic aspects and circumventing resistance, selection of the appropriate repurposed drug/drug combinations can pave the way for the development and/or refinement of liposome-based delivery strategies¹⁰ for the selective targeting of this organelle in OSCC cells^9,11.

Biography:

He is a Professor Higher Academic Grade in the School of Biosciences and Technology, VIT, Vellore, India. He has 23.75 years of teaching and research experience in Biomedical Sciences, Biotechnology and Environmental disciplines. He received his masters and Ph.D. in SIUE, IL, USA and the University of Cincinnati, OH, USA. He was a PDF at the University of Texas at Austin and Rutgers University, USA. P.K. Suresh has authored/co-authored 67 publications (h-index -17; citation index - 892). He has been a resource person and coordinator in FDPs and in International Conferences. He is working on drug development and delivery systems.