ABSTRACT
A set of N,N'-disubstituted sulfamides and sodium cyclamate have been tested for their inhibitory action against six isoforms of carbonic anhydrase (CA, EC 4.2.1.1) found in the brain, that is, CA I, CA II, CA VII, CA IX, CA XII and CA XIV, some of which are involved in epileptogenesis. The biological data showed interesting results for CA VII inhibition, the isozyme thought to be a novel antiepileptic target. Strong CA VII inhibitors, with Ki values in the low nanomolar-subnanomolar range were identified. Some of these derivatives showed selectivity for inhibition of CA VII versus the ubiquitous isoform CA II, for which the Ki values were in the micromolar range. Molecular modeling approaches were employed to understand the binding interactions between these compounds and the two CA isoforms, since the mechanism of action of such disubstituted sulfamides was not yet investigated by means of X-ray crystallography.
Subject(s)
Anticonvulsants/chemical synthesis , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrases/chemistry , Sulfonamides/chemical synthesis , Amino Acid Motifs , Anticonvulsants/chemistry , Binding Sites , Carbonic Anhydrase Inhibitors/chemistry , Cyclamates/chemistry , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Kinetics , Molecular Docking Simulation , Molecular Sequence Data , Protein Binding , Protein Structure, Secondary , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
A set of sulfamides and sulfamates were synthesized and tested against several isoforms of carbonic anhydrase: CA I, CA II, CA VII, CA XII and CA XIV. The biological assays showed a broad range of inhibitory activity, and interesting results were found for several compounds in terms of activity (Ki <1µm) and selectivity: some aromatic sulfamides are active against CA I, CA II and/or CA VII; while they are less active in CA XII and CA XIV. On the other hand, bulky sulfamides are selective to CA VII. To understand the origin of the different inhibitory activity against each isozyme we used molecular modeling techniques such as docking and molecular dynamic simulations.
Subject(s)
Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrases/chemistry , Sulfonamides/chemistry , Binding Sites , Carbonic Anhydrase I/antagonists & inhibitors , Carbonic Anhydrase I/metabolism , Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase II/metabolism , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/metabolism , Carbonic Anhydrases/metabolism , Catalytic Domain , Humans , Molecular Docking Simulation , Protein Binding , Sulfonamides/chemical synthesis , Sulfonamides/metabolismABSTRACT
Sixteen aromatic and aliphatic sulfamides and sulfamates were synthesized and tested in their inhibition to carbonic anhydrase CAII activity. The weaker inhibition pattern shown by sulfamides as compared to sulfamates is interpreted in this research by means of molecular modeling techniques, including known inhibitors (topiramate and its sulfamide cognate) in the analysis. The results nicely explain the origin of the inhibitory activity, which is not only related to positive interactions of the ligand with the active site residues but also to the solvation pattern characteristic of each ligand.
