Inhibition of mammalian DHFR can be discounted, since none of these compounds inhibited this enzyme.
High throughput screening of a compound library against this enzyme and bovine cathepsin B (BtCatB) identified four novel inhibitor classes broadly classified into 3 groups depending on the warhead-types, namely thiosemicarbazones (118, 119), nitriles (120), and semicarbazones (121).
Besides its physiological role in the detoxification of polycyclic aromatic compounds, the activity of this enzyme can be deleterious because it generates mutagenic metabolites and reactive oxygen species (ROS).
Additionally, by measuring neuraminidase activity with the neuraminidase assay kit it was found that the compounds produced inhibitory activity on this enzyme.
These compounds are nontypical substrates for this enzyme because of hydroxyl group configuration.
Although none of the compounds tested here contained a free sulfonamide group (SO2NH2), which is the typical zinc binding function that binds directly to the Zn2+ metal center of CA, still all compounds were able to inhibit this enzyme.
This compound was thought to render this enzyme complex inactive in M. tuberculosis and was subsequently proposed as an alternative working model for Rv1248c, which was believed to be responsible for the nonoxidative decarboxylation of α-ketogluturate to SSA.
This enzyme converts cortisone (compound E) to the anti-inflammatory steroid cortisol (compound F).
Therefore, GSNOR has an important role in regulating intracellular SNOs and, subsequently, the function of these compounds [ 11], while dysregulation of this enzyme can lead to deleterious effects as observed in respiratory and other diseases [ 12, 13].
It will be interesting to determine how this compound inhibits enzyme activity, as it likely hits a unique feature of OCRL/INPP5B not present in other 5-phosphatases.
