3D-QSAR, E-pharmacophore and molecular docking to explore substituted sulfonamides as carbonic anhydrase inhibitors in epilepsy

Abstract

Background- A series of aromatic sulfonamides incorporating coumarin as a lead were designed a for epilepsy target. Carbonic anhydrase is an influential target for the expansion of lead to treat epilepsy. Experimentally known carbonic anhydrase determents were identified to develop ligand based pharmacophore for anticonvulsant model. The X-ray crystallographic make-up of carbonic anhydrases with several inhibitors were utilized to develop ten energy optimized structure based (E- pharmacophore model). Pharmacophore matched candidates were utilized for docking to reclaim hits with scaffolds. The molecules having diverse structures, high docking score and low binding energy for various crystal structures of carbonic anhydrase were selected as final hits (leads). DFT is utilized to get electronic features of hits. The docking study of ligands by discovery studio had helped to establish binding interactions. The known carbonic anhydrase was reused for the development of pharmacophore hypothesis DHHRR. Based on Insilco process we came across structurally diverse hits as noncompetitive carbonic anhydrase inhibitors with better ADME. The best three hits 4, 6 and 17 were nontoxic and were selective carbonic anhydrase inhibitors with the IC50 values respectively (IC50 2.01, 2.59, 2.469). The study describes that the combined pharmacophore appeal to identify various hits which have good binding affinity for the active site of enzyme in all feasible bioactive conformations.