Rational design and insilico evaluation of 2-amino-5-methylthiazole derivatives as potent EGFR inhibitors for colorectal cancer therapy

Colorectal cancer (CRC) has become a major universal health burden, making a sustainable difference to cancer-related morbidity and fatalities worldwide. Its increasing incidence is closely associated with ageing populations, sedentary lifestyles, poor dietary habits, obesity, smoking, and other environmental and genetic risk factors. Pathway Signalling in colorectal cancer is primarily mediated by the receptor for the epidermal growth factor (EGFR), which has been identified as a major contributor to tumor development and cellular proliferation, haematochezia, alteration in bowel movement patterns, decrease in body weight, discomfort in the abdominal region, jaundice, abdominal swelling or pain in the liver, and difficulty in breathing. The current study uses ligand- and structure-based in silico methods to find a possible anti-colorectal cancer agent. A library of 676 substituted 2-amino-5-methylthiazole derivatives was rationally designed through structural modifications. The novelty lies in integrating extensive pharmacophore, QSAR, and dynamics analysis for targeted EGFR inhibition, selecting 250 compounds with predicted high activity. ADMET profiling refined these to 88 candidates with favourable drug-likeness. These compounds were docked against EGFR (PDB ID: 1M17), where Compound 26d showed superior binding energy compared to Gefitinib. Validation of the docking protocol included re-docking native ligands, ensuring reliability. MD simulations confirmed its stability and favourable pharmacokinetic features, highlighting its potential to inhibit EGFR-mediated colorectal cancer signalling, with experimental validation pending for future studies.