Dual inhibition strategy against EGFR utilizing quercetin and 5-fluorouracil: A computational analysis for oral...

Oral squamous cell carcinoma (OSCC) is a common cancer that generally has limited efficacy to standard chemotherapy. The epidermal growth factor receptor (EGFR) is a critical therapeutic target due to its role in cellular proliferation and survival. 5-Fluorouracil (5-FU) is commonly utilised in the management of OSCC; however, since it is not particularly engineered to target EGFR, adjunctive EGFR-targeted therapy approaches may improve treatment success. Quercetin, a natural flavonoid, demonstrates anticancer properties by inhibiting EGFR and may augment therapy success when used alongside 5-FU.

We acquired the protein structure (PDB ID: 7AEI) and configured it in PyMOL. We received the ligands 5-FU (PubChem CID: 3385) and Quercetin (PubChem CID: 5280343) from PubChem and then made them smaller in UCSF Chimera. We utilized PLIP to look at protein-ligand interactions and AutoDock 4.2 to dock. We used the YASARA program (AMBER14 force field) to do molecular dynamics simulations for 100 ns in NPT conditions. We examined the trajectories for RMSD, RMSF, hydrogen bonding, radius of gyration (Rg), secondary structure content, and dynamic cross-correlation maps (DCCM).

Docking analysis indicated that Quercetin demonstrated a superior binding affinity for EGFR (-6.73 kcal/mol) relative to 5-Fluorouracil (5-FU) (-5.72 kcal/mol), as well as more stable interactions with critical EGFR residues, such as Lys745 and Met793. Molecular dynamics (MD) simulations further revealed that Quercetin diminished conformational fluctuations and maintained protein compactness, signifying improved structural stability of the EGFR complex. Furthermore, the Quercetin-5-FU combination demonstrated enhanced correlated movements and improved maintenance of secondary structural components compared to 5-FU alone, suggesting that Quercetin may provide a complementary EGFR-directed stabilizing mechanism alongside standard chemotherapy.

Our research indicates that Quercetin serves as a promising EGFR-interacting compound and potential chemosensitizer, complementing conventional 5-FU therapy through enhanced receptor stabilization and modulation of EGFR-associated dynamics. Nonetheless, as the current results stem from molecular docking and MD simulations under optimal ligand-protein binding conditions, additional pharmacokinetic and experimental validation is required to ascertain whether physiologically attainable quercetin concentrations, given its established low bioavailability, can replicate these effects in vivo. These findings underscore the efficacy of bioinformatics-based methodologies in rational drug discovery and advocate for additional exploration of Quercetin-5-FU combinations for OSCC treatment.