Structural determinants for the inhibitory ligands of orotidine-5′-monophosphate decarboxylase
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- 作者：Maria Elena Meza-Avina ; Lianhu Wei ; Yan Liu ; Ewa Poduch ; Angelica M. Bello ; Ram K. Mishra ; Emil F. Pai ; Lakshmi P. Kotra
- 关键词：De novo nucleotide synthesis ; Orotidine monophosphate decarboxylase ; Pharmacophore ; Nucleotide inhibitors ; Non-nucleotide inhibitors
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2010
- 出版时间：1 June 2010
- 年：2010
- 卷：18
- 期：11
- 页码：4032-4041
- 全文大小：1004 K
文摘
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.