| Abstract [eng] |
Potential drugs should have high binding affinity, specificity, and selectivity for one isoform of human carbonic anhydrase and should not inhibit other important non-target isoforms. One of the main reasons for the need of selective inhibitors of carbonic anhydrase isoforms is to ensure that the potential drug does not cause side effects and toxic effects. One of the most popular CA inhibitors that currently are under investigation are sulfonamide-based compounds. The aim of this study was to investigate the recognition, binding affinity, and selectivity of sulfonamide-based compounds for the human carbonic anhydrase II (CA II) isoform. The work was prepared at the Department of Biothermodynamics and Drug Design of the Institute of Biotechnology of Vilnius University. The analyzed data are obtained from the ligand library developed and investigated by this Department. Performed investigation on the structure-affinity and structure-selectivity correlations has shown that the introduction of a sulfanyl or a sulfonyl group to link benzenesulfonamide para substituents to the benzene ring increases the binding affinity of the ligands for the CA II isoform. The introduction of either a sulfonyl or sulfanyl group to link benzenesulfonamide to the para substituents does not in itself significantly improve the selectivity for CA II, but the substituents attached through those functional groups affect the selectivity profile. The use of a sulfonyl group to link substituents in the para position increases the binding affinity for CA II more than the sulfanyl group. Substitution of the sulfanyl group with a sulfinyl group by linking the substituents in the para position of the benzenesulfonamide significantly reduces the binding affinity to CA II. The use of an amine functional group at the para position of the benzenesulfonamide to link the substituents to the benzene ring improves the selectivity for CA II, but decreases the binding affinity with CA II. The introduction of nitrogen-containing functional groups such as amine, amide, pyrrole, imidazole, pyridine, pyrimidine or pyrimidone in the substituents at the para or meta position of benzenesulfonamide helps to improve the selectivity for CA II. The introduction of chlorine at the ortho position of benzenesulfonamide increases the binding affinity for CA II and slightly improves selectivity for CA II. Analysis of the molecular docking results and the predicted binding conformations at the CA II active site has shown that benzenesulfonamides containing chlorine at ortho position and pyrrole, imidazole, pyridine or pyrimidine ring at the meta position could provide a basis for a novel structures of inhibitors. Optimization of these structures to achieve high binding affinity and selectivity for CA II could be done by introducing substituents at the para position of the benzenesulfonamide and by attaching additional groups to pyrrole, imidazole, pyridine or pyrimidine ring at the meta position. |
