title: Structure-Activity Relationships of Benzenesulfonamide-Based Inhibitors towards Carbonic Anhydrase Isoform Specificity.
abstract: Carbonic anhydrases (CAs) are implicated in a wide range of diseases, including the upregulation of isoforms CA IX and XII in many aggressive cancers. However, effective inhibition of disease-implicated CAs should minimally affect the ubiquitously expressed isoforms, including CA I and II, to improve directed distribution of the inhibitors to the cancer-associated isoforms and reduce side effects. Four benzenesulfonamide-based inhibitors were synthesized by using the tail approach and displayed nanomolar affinities for several CA isoforms. The crystal structures of the inhibitors bound to a CA IX mimic and CA II are presented. Further in silico modeling was performed with the inhibitors docked into CA I and XII to identify residues that contributed to or hindered their binding interactions. These structural studies demonstrated that active-site residues lining the hydrophobic pocket, especially positions 92 and 131, dictate the positional binding and affinity of inhibitors, whereas the tail groups modulate CA isoform specificity. Geometry optimizations were performed on each ligand in the crystal structures and showed that the energetic penalties of the inhibitor conformations were negligible compared to the gains from active-site interactions. These studies further our understanding of obtaining isoform specificity when designing small molecule CA inhibitors.
authors.affiliation: Department of, Biochemistry and Molecular Biology, College of Medicine, University of Florida, P. O. Box 100245, Gainesville, FL, 32610, USA.
authors.forename: Avni
authors.initials: A
authors.lastname: Bhatt
authors.affiliation: Department of, Biochemistry and Molecular Biology, College of Medicine, University of Florida, P. O. Box 100245, Gainesville, FL, 32610, USA.
authors.forename: Brian P
authors.identifier: http://orcid.org/0000-0002-5571-8058
authors.initials: BP
authors.lastname: Mahon
authors.affiliation: Department of Chemistry, College of Liberal Arts and Sciences, University of Florida, P. O. Box 117200, Gainesville, FL postCode/>32610, USA.|CAPES Foundation, Ministry of Education of Brazil, Brasília DF, 70040-020, Brazil.
authors.forename: Vinicius Wilian D
authors.identifier: http://orcid.org/0000-0002-4739-5447
authors.initials: VW
authors.lastname: Cruzeiro
authors.affiliation: Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, Université de Reims Champagne-Ardenne, UFR Pharmacie, 51 Rue Cognacq-Jay, 51096, Reims Cedex, France.|Dipartimento di Farmacia, Università "G. d'Annunzio", Via dei Vestini, 66100, Chieti, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Cornelio
authors.affiliation: Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, Université de Reims Champagne-Ardenne, UFR Pharmacie, 51 Rue Cognacq-Jay, 51096, Reims Cedex, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Laronze-Cochard
authors.affiliation: Laboratorio de Chimica Bioinorganica, Room 188, Universita degli Studi di Firenze, Via della Lastruccia 3, 50019, Sesto Fiorentino, Florence, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Ceruso
authors.affiliation: Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, Université de Reims Champagne-Ardenne, UFR Pharmacie, 51 Rue Cognacq-Jay, 51096, Reims Cedex, France.
authors.forename: Janos
authors.initials: J
authors.lastname: Sapi
authors.affiliation: School of Chemistry, The University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
authors.forename: Graham A
authors.initials: GA
authors.lastname: Rance
authors.affiliation: School of Chemistry, The University of Nottingham, University Park, Nottingham, NG7 2RD, UK.
authors.forename: Andrei N
authors.identifier: http://orcid.org/0000-0001-7738-4098
authors.initials: AN
authors.lastname: Khlobystov
authors.affiliation: Dipartimento di Farmacia, Università "G. d'Annunzio", Via dei Vestini, 66100, Chieti, Italy.
authors.forename: Antonella
authors.identifier: http://orcid.org/0000-0002-5391-7520
authors.initials: A
authors.lastname: Fontana
authors.affiliation: Department of Chemistry, College of Liberal Arts and Sciences, University of Florida, P. O. Box 117200, Gainesville, FL postCode/>32610, USA.
authors.forename: Adrian
authors.identifier: http://orcid.org/0000-0003-3963-8784
authors.initials: A
authors.lastname: Roitberg
authors.affiliation: Laboratorio de Chimica Bioinorganica, Room 188, Universita degli Studi di Firenze, Via della Lastruccia 3, 50019, Sesto Fiorentino, Florence, Italy.
authors.forename: Claudiu T
authors.identifier: http://orcid.org/0000-0003-4262-0323
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Department of, Biochemistry and Molecular Biology, College of Medicine, University of Florida, P. O. Box 100245, Gainesville, FL, 32610, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: McKenna
mesh_terms: D001665:Binding Sites; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D062105:Molecular Docking Simulation; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D000096926:Benzenesulfonamides
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D020033:Protein Isoforms; D013449:Sulfonamides; D000096926:Benzenesulfonamides
keywords: X-ray crystallography; benzenesulfonamide; carbonic anhydrase; selective inhibition; small molecule