1 research outputs found
Novel Cytidine-Based Orotidine-5′-Monophosphate Decarboxylase Inhibitors with an Unusual Twist
Orotidine-5′-monophosphate decarboxylase (ODCase)
is an
interesting enzyme with an unusual catalytic activity and a potential
drug target in <i>Plasmodium falciparum</i>, which causes
malaria. ODCase has been shown to exhibit unusual and interesting
interactions with a variety of nucleotide ligands. Cytidine-5′-monophosphate
(CMP) is a poor ligand of ODCase, and CMP binds to the active site
of ODCase with an unusual orientation and conformation. We designed
N3- and N4-modified CMP derivatives as novel ligands to ODCase. These
novel CMP derivatives and their corresponding nucleosides were evaluated
against <i>Plasmodium falciparum</i> ODCase and parasitic
cultures, respectively. These derivatives exhibited improved inhibition
of the enzyme catalytic activity, displayed interesting binding conformations
and unusual molecular rearrangements of the ligands. These findings
with the modified CMP nucleotides underscored the potential of transformation
of poor ligands to ODCase into novel inhibitors of this drug target