Inhibition of carbonic anhydrase-II by sulfamate and sulfamide groups: an investigation involving direct thermodynamic binding measurements.
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.
Klinger
Alexandra L
AL
Research & Early Development, Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA.
McComsey
David F
DF
Smith-Swintosky
Virginia
V
Shank
Richard P
RP
Maryanoff
Bruce E
BE
D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry*; D004148:Dioxolanes / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D013451:Sulfonic Acids / Q000737:chemistry*; D013816:Thermodynamics
D002257:Carbonic Anhydrase Inhibitors; D004148:Dioxolanes; D013449:Sulfonamides; D013451:Sulfonic Acids; C005741:sulfamic acid; D024402:Carbonic Anhydrase II