Two-prong inhibitors for human carbonic anhydrase II.
The enzyme inhibitors are usually designed by taking into consideration the overall dimensions of the enzyme's active site pockets. This conventional approach often fails to produce desirable affinities of inhibitors for their cognate enzymes. To circumvent such constraints, we contemplated enhancing the binding affinities of inhibitors by attaching tether groups, which would interact with the surface exposed amino acid residues. This strategy has been tested for the inhibition of human carbonic anhydrase II. Benzenesulfonamide serves as a weak inhibitor for the enzyme, but when it is conjugated to iminodiacetate-Cu2+ (which interacts with the surface-exposed His residues) via a spacer group, its binding affinity is enhanced by about 2 orders of magnitude. This "two-prong" approach is expected to serve as a general strategy for converting weak inhibitors of enzymes into tight-binding inhibitors.
Department of Chemistry, Biochemistry & Molecular Biology, North Dakota State University, Fargo, North Dakota 58105, USA.
Bidhan C
BC
Roy
Abir L
AL
Banerjee
Michael
M
Swanson
Xiao G
XG
Jia
Manas K
MK
Haldar
Sanku
S
Mallik
D K
DK
Srivastava
D001665:Binding Sites; D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D002614:Chelating Agents; D011994:Recombinant Proteins; D013449:Sulfonamides; D003300:Copper; D024401:Carbonic Anhydrase I