title: Intrinsic Thermodynamics and Structures of 2,4- and 3,4-Substituted Fluorinated Benzenesulfonamides Binding to Carbonic Anhydrases.
abstract: The goal of rational drug design is to understand structure-thermodynamics correlations in order to predict the chemical structure of a drug that would exhibit excellent affinity and selectivity for a target protein. 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 I, CA II, CA VII, CA IX, CA XII, and CA XIII. The binding enthalpies of compounds possessing similar chemical structures and affinities were found to be very different, spanning a range from -90 to +10 kJ mol-1, 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 pKavalues of the compounds were measured spectrophotometrically, and the protonation enthalpies were measured by isothermal titration calorimetry (ITC). Herein we describe the development of meta- or ortho-substituted fluorinated benzenesulfonamides toward the highly potent compound 10 h, which exhibits an observed dissociation constant value of 43 pm and an intrinsic dissociation constant value of 1.1 pm toward CA IX, an anticancer target that is highly overexpressed in various tumors. Fluorescence thermal shift assays, ITC, and X-ray crystallography were all applied in this work.
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, 10257, Lithuania.
authors.forename: Asta
authors.initials: A
authors.lastname: Zubrienė
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, 10257, Lithuania.
authors.forename: Alexey
authors.initials: A
authors.lastname: Smirnov
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, 10257, Lithuania.
authors.forename: Virginija
authors.initials: V
authors.lastname: Dudutienė
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, 10257, Lithuania.
authors.forename: David D
authors.initials: DD
authors.lastname: Timm
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, 10257, Lithuania.
authors.forename: Jurgita
authors.initials: J
authors.lastname: Matulienė
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, 10257, Lithuania.
authors.forename: Vilma
authors.initials: V
authors.lastname: Michailovienė
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, 10257, Lithuania.
authors.forename: Audrius
authors.initials: A
authors.lastname: Zakšauskas
authors.affiliation: Department of Protein-DNA Interactions, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, 10257, Lithuania.
authors.forename: Elena
authors.initials: E
authors.lastname: Manakova
authors.affiliation: Department of Protein-DNA Interactions, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, 10257, Lithuania.
authors.forename: Saulius
authors.initials: S
authors.lastname: Gražulis
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, Vilnius, 10257, Lithuania.
authors.forename: Daumantas
authors.identifier: 0000-0002-6178-6276
authors.initials: D
authors.lastname: Matulis
mesh_terms: D001665:Binding Sites; D002151:Calorimetry; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054879:Halogenation; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics; D000096926:Benzenesulfonamides
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D020033:Protein Isoforms; D013449:Sulfonamides; D000096926:Benzenesulfonamides
keywords: binding; enzymes; inhibitors; structure-thermodynamics relationships; sulfonamides