Targeting PD-1 in Squamous Cell Carcinoma: Flavonoid-based Therapeutics Unveiled through in silico and in vitro Approaches.

INTRODUCTION

Squamous cell carcinoma is a major public health concern, with traditional treatments such as surgery, chemotherapy, and radiation therapy frequently resulting in significant side effects. Immunotherapy targeting checkpoints such as PD-1, CTLA-4, and B7- H3 provides a more specific approach but incurs high costs due to monoclonal antibodies.

AIMS: This study aims to investigate the potential of natural flavonoids as low-toxicity, small molecule-based alternatives targeting the PD-1 immunological checkpoint for SCC treatment. It aims to identify and evaluate flavonoid compounds from the NPACT database for their efficacy through in silico and in vitro screenings.

METHODS

Employing a comprehensive in silico approach, including SBVS, Drug Likeness, Toxicity Prediction, Consensus Molecular Docking, DFT, and 300 ns MD simulations, this study screened for flavonoids with high affinity to PD-1. Identified lead molecules were further validated through in-vitro assays, such as NRU, to assess their anticancer activities.

RESULTS AND DISCUSSION: The flavonoid NPACT01407 showed high affinity for PD-1, favorable drug-like properties, low toxicity, and effective stability at the active site, along with an optimal IC50 value, highlighting its potential as an effective immunotherapeutic agent for SCC.

CONCLUSION

The study highlights the potential of the flavonoid molecule NPACT01407 as a promising candidate for the immunotherapeutic treatment of Squamous cell carcinoma. These findings provide a solid basis for further experimental validation and drug development efforts, suggesting a novel, less toxic, and cost-effective approach to cancer treatment.