Molecular insights of oxadiazole benzene sulfonamides as human carbonic anhydrase IX inhibitors: Combined molecular docking, molecular dynamics, and 3D QSAR studies

Abstract

α - CA IX isozyme over-expression in hypoxic environment becomes an attractive target for the design of inhibitors targeting cancer particularly, tumor progression and invasion. AimIn the process of designing new scaffolds, oxadiazole benzene sulfonamide leads were explored and evaluated for the selective inhibition of tumor-associated hCA IX. The chemical dataset compounds with human carbonic anhydrase IX inhibition values were subjected to QSAR study for generating validated models. ResultsThe best statistically validated model with three descriptors MATSe1, GATSm6 and MoRSEM15 was utilized for designing compounds with improved bioactivity. Further new molecules were taken over for the molecular docking studies and the best lead for molecular dynamics simulation and binding free energy studies. The outcome of the QSAR and molecular docking studies resulted in the development of lead molecules. Among the designed compounds two molecules 35a and 38a were further studied for molecular interactions and observations led to the residues of active site region involving both hydrophilic and hydrophobic interactions. ConclusionMolecular dynamics simulation studies for the lead molecule 38a in comparison to the reference provided useful structural insights. Further, fluctuations of the residues, H-bond profiles and stability analysis by RMSD, RMSF, RoG were studied. In addition, MM-PBSA and MM-GBSA also affirms the docking results. We propose the designed compound 38a as the best theoretical lead which may further be experimentally studied for selective inhibition.