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@ARTICLE{Kisonaite:205426,
author = {Kisonaite, Migle and Zubrienė, Asta and Čapkauskaitė,
Edita and Smirnov, Alexey and Smirnovienė, Joana and
Kairys, Visvaldas and Michailovienė, Vilma and Manakova,
Elena and Gražulis, Saulius and Matulis, Daumantas},
title = {{I}ntrinsic {T}hermodynamics and {S}tructure {C}orrelation
of {B}enzenesulfonamides with a {P}yrimidine {M}oiety
{B}inding to {C}arbonic {A}nhydrases {I}, {II}, {VII},
{XII}, and {XIII}},
journal = {PLoS one},
volume = {9},
number = {12},
issn = {1932-6203},
address = {Lawrence, Kan.},
publisher = {PLoS},
reportid = {PUBDB-2015-00003},
pages = {1-26},
year = {2014},
note = {OA},
abstract = {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.},
cin = {EMBL-User},
ddc = {500},
cid = {I:(DE-H253)EMBL-User-20120814},
pnm = {DORIS Beamline K1.1 (POF2-54G13) / MOBILI - Strengthening
and Sustaining the European Perspectives of Molecular
Biotechnology in Lithuania (245721)},
pid = {G:(DE-H253)POF2-K1.1-20130405 / G:(EU-Grant)245721},
experiment = {EXP:(DE-H253)D-K1.1-20150101},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000346611400031},
pubmed = {pmid:25493428},
doi = {10.1371/journal.pone.0114106},
url = {https://bib-pubdb1.desy.de/record/205426},
}