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In this study we explored the contribution of added functionalities of benzenesulfonamide inhibitors to the intrinsic binding affinity, enthalpy, and entropy for recombinant human carbonic anhydrases (CA) CA\u2005I, CA\u2005II, CA\u2005VII, CA\u2005IX, CA\u2005XII, and CA\u2005XIII. The binding enthalpies of compounds possessing similar chemical structures and affinities were found to be very different, spanning a range from \u221290 to +10\u2005kJ\u2009mol<jats:sup>\u22121<\/jats:sup>, and are compensated by a similar opposing entropy contribution. The intrinsic parameters of binding were determined by subtracting the linked protonation reactions. The sulfonamide group p<jats:italic>K<\/jats:italic><jats:sub>a<\/jats:sub> values of the compounds were measured spectrophotometrically, and the protonation enthalpies were measured by isothermal titration calorimetry (ITC). Herein we describe the development of <jats:italic>meta<\/jats:italic>\u2010 or <jats:italic>ortho<\/jats:italic>\u2010substituted fluorinated benzenesulfonamides toward the highly potent compound <jats:bold>10\u2009h<\/jats:bold>, which exhibits an observed dissociation constant value of 43\u2005p<jats:sc>m<\/jats:sc> and an intrinsic dissociation constant value of 1.1\u2005p<jats:sc>m<\/jats:sc> toward CA\u2005IX, an anticancer target that is highly overexpressed in various tumors. Fluorescence thermal shift assays, ITC, and X\u2010ray crystallography were all applied in this work.<\/jats:p>","DOI":"10.1002\/cmdc.201600509","type":"journal-article","created":{"date-parts":[[2016,12,21]],"date-time":"2016-12-21T08:20:16Z","timestamp":1482308416000},"page":"161-176","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Intrinsic Thermodynamics and Structures of 2,4\u2010 and 3,4\u2010Substituted Fluorinated Benzenesulfonamides Binding to Carbonic Anhydrases"],"prefix":"10.1002","volume":"12","author":[{"given":"Asta","family":"Zubrien\u0117","sequence":"first","affiliation":[{"name":"Department of Biothermodynamics and Drug Design Institute of Biotechnology Life Sciences Center Vilnius University  Saul\u0117tekio\u20057 Vilnius 10257 Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey","family":"Smirnov","sequence":"additional","affiliation":[{"name":"Department of 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