Computational investigation of imidazo[2,1-b]oxazole derivatives as potential mutant BRAF kinase inhibitors: 3D-QSAR, molecular docking, molecular dynamics simulation, and ADMETox studies

Abstract

BRAF inhibitors are known to be an effective therapeutic target for treating melanoma and other types of cancer. Using 3D-QSAR, molecular docking, and MD simulations, this study evaluated various imidazo[2,1-b]oxazole derivatives that function as mutant BRAF kinase inhibitors. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) were used to create the 3D-QSAR models. CoMSIA/SEHA model has solid predictive power across several models (Q² = 0.578; R² = 0.828; R²_pred = 0.74) and is the best model according to the numerous field models generated. The created model's predictive power was evaluated through external validation using a test set. CoMSIA/SEHA contour maps collect information that can be used to identify critical regions with solid anticancer activity. We developed four inhibitors with high predicted activity due to these observations. ADMET prediction was used to assess the toxicity of the proposed imidazo[2,1-b]oxazole compounds. The predictive molecules (T₁-T₄) demonstrated good ADMET properties, excluding the toxic active compounds 11r from the database. Molecular docking was also used to determine the patterns and modes of interactions between imidazo[2,1-b]oxazole ligands and receptors, which revealed that the proposed imidazo[2,1-b]oxazole scaffold was stable in the receptor's active site (PDB code: 4G9C). The suggested compounds (T1-T4) were subjected to molecular dynamics simulations lasting 100 ns to determine their binding free energies. The results showed that T₂ had a more favorable binding free energy (-149.552 kJ/mol) than T₁ (-112.556 kJ/mol), T₃ (-115.503 kJ/mol), and T₄ (-102.553 kJ/mol). The results suggest that the imidazo[2,1-b]oxazole compounds investigated in this study have potential as inhibitors of BRAF kinase and could be further developed as anticancer drugs. Highlights22 imidazo[2,1-b]oxazole compounds were subjected to research on three-dimensional quantitative conformational relationships.Using contour maps from 3D-QSAR models as a guide was used to figure out the areas and strategies for structural optimization.Combined molecular docking, molecular dynamics simulations, and binding free energy calculations to verify the inhibitor activity of the proposed 22 imidazo[2,1-b]oxazole compounds.Four potential B-RAF Kinase inhibitors were discovered, providing theoretical clues for developing a highly anticancer agent.Communicated by Ramaswamy H. Sarma.

Keywords: 3D-QSAR; ADMET; Anticancer; BRAF inhibitors; molecular modeling.