TY  - JOUR
AU  - Kisonaite, Migle
AU  - Zubrienė, Asta
AU  - Čapkauskaitė, Edita
AU  - Smirnov, Alexey
AU  - Smirnovienė, Joana
AU  - Kairys, Visvaldas
AU  - Michailovienė, Vilma
AU  - Manakova, Elena
AU  - Gražulis, Saulius
AU  - Matulis, Daumantas
TI  - Intrinsic Thermodynamics and Structure Correlation of Benzenesulfonamides with a Pyrimidine Moiety Binding to Carbonic Anhydrases I, II, VII, XII, and XIII
JO  - PLoS one
VL  - 9
IS  - 12
SN  - 1932-6203
CY  - Lawrence, Kan.
PB  - PLoS
M1  - PUBDB-2015-00003
SP  - 1-26
PY  - 2014
N1  - OA
AB  - The early stage of drug discovery is often based on selecting the highest affinitylead compound. To this end the structural and energetic characterization of thebinding reaction is important. The binding energetics can be resolved into enthalpicand entropic contributions to the binding Gibbs free energy. Most compoundbinding reactions are coupled to the absorption or release of protons by the proteinor the compound. A distinction between the observed and intrinsic parameters ofthe binding energetics requires the dissection of the protonation/deprotonationprocesses. Since only the intrinsic parameters can be correlated with molecularstructural perturbations associated with complex formation, it is these parametersthat are required for rational drug design. Carbonic anhydrase (CA) isoforms areimportant therapeutic targets to treat a range of disorders including glaucoma,obesity, epilepsy, and cancer. For effective treatment isoform-specific inhibitors areneeded. In this work we investigated the binding and protonation energetics ofsixteen [(2-pyrimidinylthio)acetyl]benzenesulfonamide CA inhibitors usingisothermal titration calorimetry and fluorescent thermal shift assay. The compoundswere built by combining four sulfonamide headgroups with four tailgroups yielding16 compounds. Their intrinsic binding thermodynamics showed the limitations ofthe functional group energetic additivity approach used in fragment-based drugdesign, especially at the level of enthalpies and entropies of binding. Combinedwith high resolution crystal structural data correlations were drawn between thechemical functional groups on selected inhibitors and intrinsic thermodynamicparameters of CA-inhibitor complex formation.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000346611400031
C6  - pmid:25493428
DO  - DOI:10.1371/journal.pone.0114106
UR  - https://bib-pubdb1.desy.de/record/205426
ER  -