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Chembiochem. 2017 Jan 17;18(2):213-222. doi: 10.1002/cbic.201600513. Epub 2016 Dec 22.

Structure-Activity Relationships of Benzenesulfonamide-Based Inhibitors towards Carbonic Anhydrase Isoform Specificity.

Author information

1
Department of, Biochemistry and Molecular Biology, College of Medicine, University of Florida, P. O. Box 100245, Gainesville, FL, 32610, USA.
2
Department of Chemistry, College of Liberal Arts and Sciences, University of Florida, P. O. Box 117200, Gainesville, FL postCode/>32610, USA.
3
CAPES Foundation, Ministry of Education of Brazil, Brasília DF, 70040-020, Brazil.
4
Institut de Chimie Moléculaire de Reims, CNRS UMR 7312, Université de Reims Champagne-Ardenne, UFR Pharmacie, 51 Rue Cognacq-Jay, 51096, Reims Cedex, France.
5
Dipartimento di Farmacia, Università "G. d'Annunzio", Via dei Vestini, 66100, Chieti, Italy.
6
Laboratorio de Chimica Bioinorganica, Room 188, Universita degli Studi di Firenze, Via della Lastruccia 3, 50019, Sesto Fiorentino, Florence, Italy.
7
School of Chemistry, The University of Nottingham, University Park, Nottingham, NG7 2RD, UK.

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.

KEYWORDS:

X-ray crystallography; benzenesulfonamide; carbonic anhydrase; selective inhibition; small molecule

PMID:
27860128
DOI:
10.1002/cbic.201600513
[Indexed for MEDLINE]

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