Structural determinants for the inhibitory ligands of orotidine-5'-monophosphate decarboxylase.
In recent years, orotidine-5'-monophosphate decarboxylase (ODCase) has gained renewed attention as a drug target. As a part of continuing efforts to design novel inhibitors of ODCase, we undertook a comprehensive study of potent, structurally diverse ligands of ODCase and analyzed their structural interactions in the active site of ODCase. These ligands comprise of pyrazole or pyrimidine nucleotides including the mononucleotide derivatives of pyrazofurin, barbiturate ribonucleoside, and 5-cyanouridine, as well as, in a computational approach, 1,4-dihydropyridine-based non-nucleoside inhibitors such as nifedipine and nimodipine. All these ligands bind in the active site of ODCase exhibiting distinct interactions paving the way to design novel inhibitors against this interesting enzyme. We propose an empirical model for the ligand structure for rational modifications in new drug design and potentially new lead structures.
Meza-Avina
Maria Elena
ME
Division of Cell & Molecular Biology, University Health Network, Toronto, ON, Canada.
Wei
Lianhu
L
Liu
Yan
Y
Poduch
Ewa
E
Bello
Angelica M
AM
Mishra
Ram K
RK
Pai
Emil F
EF
Kotra
Lakshmi P
LP
D000818:Animals; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D011685:Purine Nucleotides; D011742:Pyrimidine Nucleotides
D004791:Enzyme Inhibitors; D008024:Ligands; D011685:Purine Nucleotides; D011742:Pyrimidine Nucleotides; D009964:Orotidine-5'-Phosphate Decarboxylase
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