4QSJ

Crystal structure of human carbonic anhydrase isozyme XIII with 2-chloro-4-{[(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio]acetyl}benzenesulfonamide

Summary for 4QSJ

• Entry DOI: 10.2210/pdb4qsj/pdb
• Related: 4QSA 4QSB 4QSI
• Descriptor: Carbonic anhydrase 13, ZINC ION, 2-chloro-4-{[(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)sulfanyl]acetyl}benzenesulfonamide, ... (9 entities in total)
• Functional Keywords: drug design, carbonic anhydrase, benzenesulfonamide, metal-binding, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 60962.57

Authors

Smirnov, A.,Manakova, E.,Grazulis, S. (deposition date: 2014-07-04, release date: 2015-01-21, Last modification date: 2023-11-08)

Primary citation

Kisonaite, M.,Zubriene, A.,Capkauskaite, E.,Smirnov, A.,Smirnoviene, J.,Kairys, V.,Michailoviene, V.,Manakova, E.,Grazulis, S.,Matulis, D.
Intrinsic Thermodynamics and Structure Correlation of Benzenesulfonamides with a Pyrimidine Moiety Binding to Carbonic Anhydrases I, II, VII, XII, and XIII
Plos One, 9:e114106-e114106, 2014

PubMed 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.

PubMed: 25493428
DOI: 10.1371/journal.pone.0114106

Experimental method

X-RAY DIFFRACTION (1.7 Å)