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However, effective inhibition of disease\u2010implicated CAs should minimally affect the ubiquitously expressed isoforms, including CA\u2005I and II, to improve directed distribution of the inhibitors to the cancer\u2010associated isoforms and reduce side effects. Four benzenesulfonamide\u2010based 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\u2005IX mimic and CA\u2005II are presented. Further in silico modeling was performed with the inhibitors docked into CA\u2005I and XII to identify residues that contributed to or hindered their binding interactions. These structural studies demonstrated that active\u2010site 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\u2010site interactions. These studies further our understanding of obtaining isoform specificity when designing small molecule CA inhibitors.<\/jats:p>","DOI":"10.1002\/cbic.201600513","type":"journal-article","created":{"date-parts":[[2016,11,18]],"date-time":"2016-11-18T05:21:02Z","timestamp":1479446462000},"page":"213-222","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Structure\u2013Activity Relationships of Benzenesulfonamide\u2010Based Inhibitors towards Carbonic Anhydrase Isoform Specificity"],"prefix":"10.1002","volume":"18","author":[{"given":"Avni","family":"Bhatt","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology College of Medicine University of Florida  P.\u2009O. 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