A Combined in Silico and Structural Study Opens New Perspectives on Aliphatic Sulfonamides, a Still Poorly Investigated Class of CA Inhibitors(187 views) Langella E, Esposito D, Monti SM, Supuran CT, De Simone G, Alterio V
Biology (ISSN: 2079-7737linking), 2023 Feb 10; 12
(2
): N/D-N/D.
Keywords: X-Ray Crystallography
, Aliphatic Sulfonamide
, Binding Free Energy Calculations
, Carbonic Anhydrase Inhibitors
, Structure-Based Drug Design
Affiliations: *** IBB - CNR ***
Institute of Biostructures and Bioimaging-CNR, Via Pietro Castellino 111, 80131 Naples, Italy.
Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
References: Not available.
A Combined in Silico and Structural Study Opens New Perspectives on Aliphatic Sulfonamides, a Still Poorly Investigated Class of CA Inhibitors
Aliphatic sulfonamides are an interesting class of carbonic anhydrase inhibitors (CAIs) proven to be effective for several carbonic anhydrase (CA) isoforms involved in pathologic states. Here we report the crystallographic structures of hCA II in complex with two aliphatic sulfonamides incorporating coumarin rings, which showed a good inhibition and selectivity for this isoform. Although these two molecules have a very similar chemical structure, differing only in the substitution of the two aliphatic hydrogen atoms with two fluorine atoms, they adopt a significantly different binding mode within the enzyme active site. Theoretical binding free energy calculations, performed to rationalize these data, showed that a delicate balance of electrostatic and steric effects modulate the protein-ligand interactions. Data presented here can be fruitfully used for the rational design of novel and effective isozyme-specific inhibitor molecules.
A Combined in Silico and Structural Study Opens New Perspectives on Aliphatic Sulfonamides, a Still Poorly Investigated Class of CA Inhibitors