Structural determinants for the inhibitory ligands of orotidine-5′-monophosphate decarboxylase |
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| Authors: | Maria Elena Meza-Avina Lianhu Wei Yan Liu Ewa Poduch Angelica M Bello Ram K Mishra Emil F Pai Lakshmi P Kotra |
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| Institution: | 1. Center for Molecular Design and Preformulations and Division of Cell & Molecular Biology, Toronto General Research Institute/University Health Network, Toronto, ON, Canada M5G 1L7;2. Departments of Pharmaceutical Sciences and Chemistry, University of Toronto, Canada;3. Division of Cancer Genomics and Proteomics, Ontario Cancer Institute/University Health Network, Toronto, ON, Canada M5G 1L7;4. Departments of Biochemistry, Medical Biophysics, and Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8;5. McLaughlin Center for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada;6. Department of Chemistry & Biochemistry, The University of North Carolina at Greensboro, Greensboro, NC 27412, USA |
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| 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. |
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