3D-QSAR modeling with selection of local reactive descriptors (LRD) and molecular docking studies on...

The understanding of the interaction mechanism between ligands and receptors depends on the performance of the descriptors. In this study, the electrophilic and nucleophilic interactions of diarylpyrazole-benzenesulfonamide derivatives active on human carbonic anhydrase in 3D space were analyzed using different types of Local Reactivity Descriptors (LRDs). Three different classes of descriptors used in the Molecular Conformer Electron Topology (MCET) method: (1) Atomic charge, (2) Frontier Molecular Orbital (FMO) and (3) Fukui and Klopman indices. To assess the effect of changing LRD types on the ligand side, the variations in dimensions and values of the parameters on the receptor side were calculated for 3D quantitative structure-activity relationship (3D-QSAR) models. Each model was evaluated using the Leave One Out-Cross Validation (LOO-CV) method on the training set from the split molecule series and then validated on the external test set. As a result of comparing the different LRD types, a model with satisfactory values of Q² = 0.933 and R² = 0.964 was selected, which consisted of the electrostatic charge and LUMO coefficient under the Klopman Index (K_I) class. The activity changes at the interaction points between the ligand and receptor (L-R) were plotted to show the Auxiliary Group (AG) and Anti Pharmacophore Shielding (APS) groups. In addition to ligand-based drug design, the binding interactions between the ligand and the identified targets were investigated through molecular docking, one of the most widely used methods in structure-based drug design.