In silico Design and Molecular Modeling of Piperazine-Oxadiazole Appended Imidazo[2,1-b][1,3,4]Thiadiazoles as Promising RTK Inhibitors

INTRODUCTION: Cancer remains a significant global health issue, and the Epidermal Growth Factor Receptor (EGFR) is a key therapeutic target in various cancer types. This study aimed to identify new, potent EGFR inhibitors.

METHODS: In silico analysis was used to design and evaluate novel Imidazo[2,1-b][1,3,4]thiadiazole derivatives with dual pharmacophores. Molecular docking was performed using Autodock Vina 1.1.2 to assess their binding affinities to EGFR Kinase, VEGFR2, and Human HER2. Pharmacological profiling was also conducted to predict ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) and drug-likeness properties. To confirm the stability of the most promising candidates, Molecular Dynamics (MD) simulations were performed using Maestro.

RESULTS: The docking analysis revealed that all ligands exhibited favorable binding affinities toward the selected receptor tyrosine kinases (1YWN, 3POZ, and 3PP0), with binding energies ranging from -8.3 to -10.4 kcal/mol. Among the targets, 3POZ showed the strongest overall ligand interactions. Notably, Ligand 6c showed superior binding affinity with a maximum docking score of -10.4 kcal/mol (Pose 1). ADMET profiles of all the compounds showed that compounds showed drug likeness in the order of 6a > 6b > 6c as per the Lipinski Rule of Five.

DISCUSSION: The designed imidazo[2,1-b][1,3,4]thiadiazole derivatives exhibited stable binding within the EGFR kinase domain, with supportive comparative analysis against VEGFR2 and HER2. Molecular docking and 100 ns molecular dynamics simulations confirmed favorable interaction stability. ADMET profiling suggested acceptable drug-likeness and oral absorption. These findings highlight the potential of the proposed scaffolds as promising RTK inhibitors warranting further experimental validation.

CONCLUSION: This study employed molecular docking, 100 ns molecular dynamics simulations, and ADMET profiling to evaluate substituted imidazo[2,1-b][1,3,4]thiadiazole derivatives (6a-6c) targeting VEGFR2, EGFR, and HER2. Among the series, the nitro-substituted compound 6c exhibited the strongest binding affinity and most stable interactions within the kinase active sites. Molecular dynamics results confirmed stable complex formation, as evidenced by consistent RMSD and persistent hydrogen bonding. ADMET analysis indicated favorable drug-likeness and predicted oral bioavailability. Overall, compound 6c emerges as the most promising candidate for further experimental validation as a receptor tyrosine kinase inhibitor.