Novel cytidine-based orotidine-5'-monophosphate decarboxylase inhibitors with an unusual twist.

Meena K Purohit, Ewa Poduch, Lianhu William Wei, Ian Edward Crandall, Terrence To, Kevin C Kain, Emil F Pai, Lakshmi P Kotra

Center for Molecular Design and Preformulations, Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 1L7, Canada.

Journal of medicinal chemistry 2012 Nov 26

filter terms:

Orotidine-5'-monophosphate decarboxylase (ODCase) is an interesting enzyme with an unusual catalytic activity and a potential drug target in Plasmodium falciparum, 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 Plasmodium falciparum 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.

Citation

Meena K Purohit, Ewa Poduch, Lianhu William Wei, Ian Edward Crandall, Terrence To, Kevin C Kain, Emil F Pai, Lakshmi P Kotra. Novel cytidine-based orotidine-5'-monophosphate decarboxylase inhibitors with an unusual twist. Journal of medicinal chemistry. 2012 Nov 26;55(22):9988-97