• QSAR;
  • simulated annealing;
  • carbonic anhydrase II inhibitors;
  • carbonic anhydrase IX inhibitors;
  • virtual screening;
  • ADME/T profiling

A quantitative structure–activity relationship (QSAR) analysis was performed on a dataset of 62 (1,3,5-triazine-substituted) benzene sulfonamides as carbonic anhydrase II and IX inhibitors using simulated annealing-based multiple linear regression analysis. The selected QSAR model for carbonic anhydrase II inhibition (cross-validated Q2 = 0.689, inline image, inline image) showed that aromaticity, lipophilicity, electronegativity, and molecular projection in the XZ plane influence the activity, whereas that for carbonic anhydrase IX inhibition (cross-validated Q2 = 0.767, inline image, inline image) showed that activity was influenced by hydrophilicity, linker between the aromatic rings, electronegativity, and molecular weight. The QSAR model selected was internally and externally validated to define its predictability. Activity prediction of an external dataset containing nine compounds (within the same sphere of applicability) was performed to prove the models' specificity, selectivity, and sensitivity. The hypothesis in the form of the QSAR model was used for ligand-based virtual screening on the ZINC database to obtain some potential hits. Similarly, docking studies on screened hits showed that the molecules interact and orient at the catalytic site in a way similar to acetazolamide. Additionally, an absorption, distribution, metabolism, excretion, and toxicity screening was also performed, and results showed that most of the compounds that can be possible drug candidates obey the Lipinski rule of five and Jorgensen rule of three. Copyright © 2013 John Wiley & Sons, Ltd.