title: Intrinsic Thermodynamics and Structure Correlation of Benzenesulfonamides with a Pyrimidine Moiety Binding to Carbonic Anhydrases I, II, VII, XII, and XIII.
abstract: The early stage of drug discovery is often based on selecting the highest affinity lead compound. To this end the structural and energetic characterization of the binding reaction is important. The binding energetics can be resolved into enthalpic and entropic contributions to the binding Gibbs free energy. Most compound binding reactions are coupled to the absorption or release of protons by the protein or the compound. A distinction between the observed and intrinsic parameters of the binding energetics requires the dissection of the protonation/deprotonation processes. Since only the intrinsic parameters can be correlated with molecular structural perturbations associated with complex formation, it is these parameters that are required for rational drug design. Carbonic anhydrase (CA) isoforms are important therapeutic targets to treat a range of disorders including glaucoma, obesity, epilepsy, and cancer. For effective treatment isoform-specific inhibitors are needed. In this work we investigated the binding and protonation energetics of sixteen [(2-pyrimidinylthio)acetyl]benzenesulfonamide CA inhibitors using isothermal titration calorimetry and fluorescent thermal shift assay. The compounds were built by combining four sulfonamide headgroups with four tailgroups yielding 16 compounds. Their intrinsic binding thermodynamics showed the limitations of the functional group energetic additivity approach used in fragment-based drug design, especially at the level of enthalpies and entropies of binding. Combined with high resolution crystal structural data correlations were drawn between the chemical functional groups on selected inhibitors and intrinsic thermodynamic parameters of CA-inhibitor complex formation.
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius, LT-02241, Lithuania.
authors.forename: Miglė
authors.initials: M
authors.lastname: Kišonaitė
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius, LT-02241, Lithuania.
authors.forename: Asta
authors.initials: A
authors.lastname: Zubrienė
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius, LT-02241, Lithuania.
authors.forename: Edita
authors.initials: E
authors.lastname: Capkauskaitė
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius, LT-02241, Lithuania.
authors.forename: Alexey
authors.initials: A
authors.lastname: Smirnov
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius, LT-02241, Lithuania.
authors.forename: Joana
authors.initials: J
authors.lastname: Smirnovienė
authors.affiliation: Department of Bioinformatics, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius, LT-02241, Lithuania.
authors.forename: Visvaldas
authors.initials: V
authors.lastname: Kairys
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius, LT-02241, Lithuania.
authors.forename: Vilma
authors.initials: V
authors.lastname: Michailovienė
authors.affiliation: Department of Protein - DNA Interactions, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius, LT-02241, Lithuania.
authors.forename: Elena
authors.initials: E
authors.lastname: Manakova
authors.affiliation: Department of Protein - DNA Interactions, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius, LT-02241, Lithuania.
authors.forename: Saulius
authors.initials: S
authors.lastname: Gražulis
authors.affiliation: Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Graičiūno 8, Vilnius, LT-02241, Lithuania.
authors.forename: Daumantas
authors.initials: D
authors.lastname: Matulis
mesh_terms: D002257:Carbonic Anhydrase Inhibitors / Q000378:metabolism*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006878:Hydroxides / Q000378:metabolism; D015394:Molecular Structure; D011743:Pyrimidines / Q000737:chemistry*; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics; D015032:Zinc / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D006878:Hydroxides; D011743:Pyrimidines; D013449:Sulfonamides; D015032:Zinc; D000096926:Benzenesulfonamides; C030986:pyrimidine