Exploring QSAR for the Inhibitory Activity of a Large Set of Aromatic/Heterocyclic Sulfonamides toward Four Different Isoenzymes of Carbonic Anhydrase

摘要

The Carbonic Anhydrase (CA) inhibitory activities of a large number of sulfonamide derivatives toward CA isoenzyme types I, II, IV, and IX were collected and then subjected to QSAR analyses. The dataset used consisted of 343 sulfonamide derivatives with 200 calculated descriptors. For each type of isoenzyme, a separate QSAR model was obtained using multiple linear regression analysis with stepwise selection of variables. The generalization, stability, and predictivity of the models were evaluated by leave-many-out cross-validation, using an external test set and chance correlation. All the obtained models represented high statistical quality and prediction ability with q~2 and R_P~2 greater than 0.80. The relative errors of prediction were lower than 5%. By the developed models, the ligand - receptor interactions involved in the binding of sulfonamides to different CA isoenzymes were discussed. For all types of isoenzymes, the topological indices represented significant impacts on the ligand-enzyme interactions. It was found that, for CAI, the acid-base properties play a significant role whereas for CAII the coulombic interactions are controlling factors. In addition, number of thiol functional groups exhibited significant negative effect on the binding of sulfonamides to CAII. For CAIV, the hydrogen bonding interactions were detected as a major factor. Finally, for the binding of sulfonamides to CAIX, the lipophilicity, and acid-base properties were selected as highly influential parameters. ,