Molecular docking studies of some amino acid-sulfonamide conjugates as potential anticancer agents

Some amino acid-sulfonamide conjugates 9a-d/10a-d/11a-c were synthesized by a two-step reported route starting from commercially available sulfonamides, namely, sulfadiazine, sulfapyridine, and sulfanilamide. Similar to the clinically used drug acetazolamide, amino acid-sulfonamide conjugates showed inhibition against human carbonic anhydrase-I. Molecular docking studies revealed that these compounds fit well into the active site, forming hydrogen bonds (H-bonds) with the active site residues. The binding free energy for compounds 9a-d/10a-d/11a-c ranged from −6.9 to −7.8 kcal/mol, suggesting strong ligand-protein affinity. Among all, compound 10a exhibited the lowest binding energies of −7.8 kcal/mol. By establishing H-bond interactions with the active site residue Thr199 through carboxylate groups, the most promising chemical 10a was found to fit neatly into the carbonic anhydrase’s active site. The terminal carboxylate group appears to be favorable in forming additional van der Waals interaction with His200. With residue Phe91, the phenyl ring produced a π-π stacking close to the hydrophobic pocket. However, the pyridinyl group enhanced inhibitory potential as anticancer drugs by forming a π-alkyl interaction with Pro202 that made the molecule more capable of binding proteins.