Drug repurposing strategy to identify the putative leads against the Epidermal growth factor receptor (EGFR) from the USFDA-approved drug pool: Investigating the utility as an anticancer agent

EGFR is a validated drug target in Anticancer drug discovery. However, the existing issues of drug resistance, toxicities, and evolving mutations in EGFR have led to the global decline in the putative and potent anti-EGFR therapeutics. To address this gap, drug repurposing or repositioning is a valid technique for drug identification in a quick time and in an economical way. We herein employed the drug repurposing techniques from the library of 3500 approved USFDA small molecules. The initial HTVS (high-throughput virtual screening), followed by XP analysis and molecular mechanics (MMGBSA) and ADME profiling, led to the identification of Cycloguanil (antimalarial) and Metformin (antidiabetic) as the putative lead molecules with the potential to inhibit the EGFR. The top-scoring ligand was subjected to a molecular dynamics simulation study that stabilized the stability of cycloguanil within the ATP pocket of EGFR. The biological investigations further corroborated the in-silico studies. Cycloguanil inhibited the EGFR with a half maximal inhibitory concentration (IC50) of IC₅₀ of 490 nM compared to erlotinib with an IC₅₀ of 222 nM. Besides this, cycloguanil was able to halt the cell cycle progression at the G1 phase (46.54%), a peculiar feature of the kinase inhibitors that affect the CDKs and cyclins required for the passage of Cancer cells through G1. Annexin V assay revealed that cycloguanil induced profound Apoptosis in A549 cells. The lead molecules were also found to possess cytotoxicity profiles in MCF-7, A549, and HCT-116, which were reported to harbor the expression of EGFR. From the analysis, it was deduced that cycloguanil exhibited the most potent cytotoxicity towards the A549 cell with an IC50 of 6.83 μM, followed by HCT-116 with an IC50 of 9.32 μM, while in MCF-7, it exhibited an IC₅₀ of 14.82 μM. The lead molecule, cycloguanil, may plausibly serve as an important template that may be optimized by performing bioisosteric replacements, leading to a putative kinase inhibitor with a potent Anticancer profile.