Inhibition of carbonic anhydrase-II by sulfamate and sulfamide groups: an investigation involving direct thermodynamic binding measurements.

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Klinger AL, McComsey DF, Smith-Swintosky V, Shank RP, Maryanoff BE

Inhibition of carbonic anhydrase-II by sulfamate and sulfamide groups: an investigation involving direct thermodynamic binding measurements.

J Med Chem. 2006 Jun 15;49(12):3496-500.

PubMed ID

16759092 [ View in PubMed

]

Abstract

This paper examines the relative effectiveness of bioisosteric sulfamate and sulfamide derivatives for inhibition of human carbonic anhydrase-II (CA-II) by using a direct binding assay based on the ThermoFluor method (Matulis et al. Biochemistry 2005, 44, 5258). Compounds 1-10, which represent five cognate sulfamate/sulfamide pairs, were studied by ThermoFluor to obtain binding affinities (K(a) values). The corresponding dissociation constants, K(d), provide an independent measure of CA-II activity relative to commonly used K(i) values from enzyme kinetics studies. There was a sizable difference in potency between the sulfamates and sulfamides, with the sulfamides being much less potent, by factors ranging from 25 (7/8) to 1,200 (3/4). These results are consistent with our recent report that sulfamides tend to be much weaker inhibitors of CA-II than their corresponding sulfamates (Maryanoff et al. J. Med. Chem. 2005, 48, 1941). Additionally, for arylsulfamides 10-12 the K(d) values determined by ThermoFluor and the K(i) values determined from enzyme kinetics are consistent. It appears that the sulfamide group is less suitable than the sulfamate group for obtaining potent inhibition of CA-II.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Sulfamic Acid 2,3-O-(1-Methylethylidene)-4,5-O-Sulfonyl-Beta-Fructopyranose Ester	Carbonic anhydrase 2	Kd (nM)	10	N/A	N/A	Details
Topiramate	Carbonic anhydrase 2	Kd (nM)	290	N/A	N/A	Details