Affinity of Sulfamates and Sulfamides to Carbonic Anhydrase II Isoform: Experimental and Molecular Modeling Approaches

Abstract

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.

Inhibition pattern of sulfamide-related compounds in binding to carbonic anhydrase isoforms I, II, VII, XII and XIV

“…42 For CA II we used the 0.99 Å resolution crystal structure of the CA II-sulfonamide complex (2FOU), 43 as previously done when studying CA II sulfamide inhibition. 7 We also modeled the conformational mobility of the side chain of His64 residue in the docking, which is likely associated with its role as a proton shuttle in catalysis. 44 To this end, the docking was performed with the two different 'in' and 'out' conformations 44 of His64 for CA II (Fig.…”

“…47 This was found to perform better than the default Gasteiger charges in the CA II docking. 7 The structures were docked using the Lamarckian genetic algorithm (LGA) in the 'docking active site', defined through a grid centered on the CG1 atom of Val59 residue for CA I, the ND2 atom of Asn67 residue for CA II and the ND2 atom of Asn64 for CA VII. In all isozymes we used 60, 50, and 60 grid points in X, Y, Z dimensions respectively, with the default grid spacing (0.375 Å); and performed 50 docking runs.…”

“…1,5,6 Recently we reported an investigation about the weaker inhibition pattern shown by sulfamides as compared to sulfamates against CA II, and we interpreted this tendency using molecular modeling techniques. 7 Following this research, we report here the inhibitory profile of a set of sulfamides and sulfamates against several CA isoforms. The compounds reported have been previously synthesized and tested in their anticonvulsant activity.…”

Docking, CoMFA and CoMSIA studies of a series of sulfonamides derivatives as carbonic anhydrase I inhibitors

“…Gavernet and Coworkers synthesized sulfamides and sulfamates inhibitors and tested in their inhibition to carbonic anhydrase CAII activity, inhibition pattern interpreted by means of molecular modeling techniques 4 . Abdel-Hamid et al synthesized a new series of 1,3,4-thiadiazole-2-thione derivatives for the inhibition of three physiologically relevant carbonic anhydrase isozymes, the cytosolic human isozymes I and II, and the transmembrane, tumor-associated hCA IX and use docking studies of the tested compounds in order to predict the affinity and orientation of these compounds 11 .…”

“…So this is a basic reaction for respiration and transportation of CO 2 between metabolizing tissues and excretion sites 3 . CA enzymes have been classified in five distinct gene families: α-,β-,γ-, δ-, and ξ-that are present in prokaryotes and eukaryote 4,5 . There are several cytosolic forms (CA I-III, VII), four membrane-bound isozymes (CA IV, IX, XII, and XIV), one mitochondrial form (CA V), and a secreted CA isozyme, CA VI 6 .…”