Inhibition and binding studies of carbonic anhydrase isozymes I, II and IX with benzimidazo[1,2-c][1,2,3]thiadiazole-7-sulphonamides.
The binding and inhibition strength of a series of benzimidazo[1,2-c][1,2,3]thiadiazole-7-sulphonamides were determined for recombinant human carbonic anhydrase isoforms I, II, and IX. The inhibition strength was determined by a stop-flow method to measure carbon dioxide hydration. Inhibitor-enzyme binding was determined by two biophysical techniques--isothermal titration calorimetry and thermal shift assay. The co-crystal structure was determined by X-ray crystallography. Comparing the results obtained using three different inhibition and binding methods increased the accuracy of compound affinity ranking and the ability to determine compound inhibitory specificity towards a particular carbonic anhydrase isoform. In most cases, all three methods yielded the same results despite using very different approaches to measure the binding and inhibition reactions. Some of the compounds studied are submicromolar inhibitors of the isoform IX, a prominent cancer target.
Baranauskienė
Lina
L
Laboratory of Biothermodynamics and Drug Design, Institute of Biotechnology, Graičiūno 8, Vilnius, Lithuania.
Hilvo
Mika
M
Matulienė
Jurgita
J
Golovenko
Dmitrij
D
Manakova
Elena
E
Dudutienė
Virginija
V
Michailovienė
Vilma
V
Torresan
Jolanta
J
Jachno
Jelena
J
Parkkila
Seppo
S
Maresca
Alfonso
A
Supuran
Claudiu T
CT
Gražulis
Saulius
S
Matulis
Daumantas
D
D000465:Algorithms; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002151:Calorimetry / Q000379:methods; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008968:Molecular Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013830:Thiadiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D002257:Carbonic Anhydrase Inhibitors; D008024:Ligands; D011994:Recombinant Proteins; D013449:Sulfonamides; D013830:Thiadiazoles; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases