In Silico Design, Molecular Docking, Molecular dynamics simulations, and Pharmacokinetics Insights of Novel 1,3,4-Oxadiazole and 1,3,4-Thiadiazole Derivatives as Potential EGFR Inhibitors

The study investigates the promising role of new 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives (A1–A6) as potent epidermal growth factor receptor (EGFR) inhibitors, which is a crucial therapeutic target in non-small cell lung cancer (NSCLC). Using extensive in silico approaches, by combined molecular docking, molecular dynamics (MD) simulations, and ADMET profiling to assess the pharmacological potential of these compounds. Because EGFR is crucial in NSCLC, mutations in this receptor promote tumor growth and resistance to current tyrosine kinase inhibitors (TKIs) including Erlotinib. Although initially very effective, first-generation TKIs are often eventually rendered ineffective by resistance mechanisms such as T790M mutations, therefore innovative inhibitors with improved efficacy and stability are warranted. The process began with ligand preparation, which was performed through ChemDraw and Chem3D to minimize energy, and the computational evaluations were conducted using Schrödinger Suites. All compounds showed good adherence to Lipinski’s Rule of Five, indicating their drug-likeness, as shown by ADMET statistically analyzed data. The molecular docking showed that the derivatives have better binding affinities than Erlotinib and the compound A1 and A2 which have PLPfitness 90.61 and 83.77, respectively. Robust hydrogen bonding and hydrophobic interaction with the essential EGFR residues such as THR830 and THR766 was credited for these results. Molecular dynamics (MD) simulations further supported the stability of the complex, showing a 100-nanosecond trajectory with root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analyses confirming structural stability and stability of ligand binding in the A1-EGFR complex. Pharmacokinetic assessments highlighted the compounds' favorable absorption, distribution, and low cardiotoxicity risks. Candidate A1 (Caco-2, 2636.59 nm/sec, LogP, 4.19) showed the highest internal permeability as well as optimal lipophilicity and binding interactions, respectively. Specifically, Specifically, A1 shows a stable interaction with key residues in the EGFR active site during 100nm of simulation, thereby supporting its role as a selective inhibitor. Consequently, A1 emerges as a promising candidate for experimental validation and further drug development to treat EGFR-driven NSCLC. This study highlights the power of computational methods in the early stage of drug discovery.