Investigating the selectivity of metalloenzyme inhibitors.
The inhibitory activity of a broad group of known metalloenzyme inhibitors against a panel of metalloenzymes was evaluated. Clinically approved inhibitors were selected as well as several other reported metalloprotein inhibitors in order to represent a broad range of metal binding groups (MBGs), including hydroxamic acid, carboxylate, hydroxypyridinonate, thiol, and N-hydroxyurea functional groups. A panel of metalloenzymes, including carbonic anhydrase (hCAII), several matrix metalloproteinases (MMPs), angiotensin converting enzyme (ACE), histone deacetylase (HDAC-2), and tyrosinase (TY), was selected based on their clinical importance for a range of pathologies. In addition, each inhibitor was evaluated for its ability to remove Fe(3+) from holo-transferrin to gauge the ability of the inhibitors to access Fe(3+) from a primary transport protein. The results show that the metalloenzyme inhibitors are quite selective for their intended targets, suggesting that despite their ability to bind metal ions, metalloprotein inhibitors are not prone to widespread off-target enzyme inhibition activity.
Department of Chemistry and Biochemistry, University of California, San Diego , La Jolla, California 92093, United States.
Joshua A
JA
Day
Seth M
SM
Cohen
D055162:Biocatalysis / Q000187:drug effects; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004798:Enzymes / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008667:Metalloproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism
D004791:Enzyme Inhibitors; D004798:Enzymes; D006877:Hydroxamic Acids; D008667:Metalloproteins; D014442:Monophenol Monooxygenase; D007703:Peptidyl-Dipeptidase A; D020778:Matrix Metalloproteinase 2; D053508:Matrix Metalloproteinase 12; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2; D024402:Carbonic Anhydrase II