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

AbstractAbstractBRAF 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; R2pred = 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. SarmaKeywords: AnticancerBRAF inhibitors3D-QSARADMETmolecular modeling Disclosure statementThe authors reported no potential conflict of interestAuthors contributionsAll of the contributors aided the study’s inception and design. ‘Boutalaka M; El bahi S; El Alaouy MA; Koubi Y; El Khatabi K’ presented idea, draft preparation, data handling, data analysis, and writing, ‘Alaqarbeh M’ performed the calculations of molecular dynamics, writing, review, and editing, ‘Maghat H and Bouachrine M’ data analysis, study justification, reviewing, and supervision, ‘Lakhlifi T’ reviewing supervision, and project administration.Data availability statementAll the data are available.Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.