Structural determinants for the inhibitory ligands of orotidine-5′-monophosphate decarboxylase

Abstract

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.

The Epigenetic Drug 5-Azacytidine Interferes with Cholesterol and Lipid Metabolism

“…7A). Similar to 5-AzaC, incubation of HepG2 cells with pyrazofurin, a potent inhibitor of UMP synthase (38), strongly decreased UTP and CTP levels (Fig. 7A) and also provoked accumulation of LDs, which was reversed by the addition of UMP (Fig.…”

Cyano Modification on Uridine Decreases Base‐Pairing Stability and Specificity through Neighboring Disruption in RNA Duplex

“…Although the synthesis of the cnm 5 U and cn 5 U nucleosides was previously achieved, more general phosphoramidite building blocks for the solid‐phase synthesis of oligonucleotides are still required to make different scales of RNA strands. We started the synthesis of cnm 5 U from commercially available 5‐methyluridine ( 1 , Scheme ), which was fully acetyl protected; this was followed by bromination of the 5‐methyl group in the presence of N ‐bromosuccinimide (NBS) and 2,2′‐azobisisobutyronitrile (AIBN) to give 5‐bromomethyluridine ( 3 ).…”

“…5‐Cyanouridine (12) : Compound 11 (5.81 g, 10 mmol) was dissolved in 7 n NH 3 /MeOH (50 mL) at room temperature, and the mixture was stirred for 12 h. The solvent was removed by repeat evaporation with the re‐addition of MeOH to remove all ammonia. The residue was purified by silica gel chromatography to give compound 12 (1.80 g, 6.69 mmol, 67 %) as a white solid.…”

Novel Interactions of Fluorinated Nucleotide Derivatives Targeting Orotidine 5′-Monophosphate Decarboxylase

“…10,11,12 Interestingly, two non-nucleoside inhibitors, nifedipine and nimodipine, inhibit ODCase competitively with modest potency (Figure 2). 13,14 …”