Division of Cell & Molecular Biology, University Health Network, Toronto, ON, Canada.
Bioorg Med Chem. 2010 Jun 1;18(11):4032-41. doi: 10.1016/j.bmc.2010.04.017. Epub 2010 Apr 9.
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.
近年来，乳清酸-5'-单磷酸脱羧酶（ODCase）作为药物靶点重新引起了人们的关注。作为继续设计新型 ODCase 抑制剂的努力的一部分，我们对 ODCase 的有效、结构多样的配体进行了全面研究，并分析了它们在 ODCase 活性部位的结构相互作用。这些配体包括吡唑或嘧啶核苷酸，包括吡唑呋喃苷、巴比妥核糖核苷和 5-氰尿苷的单核苷酸衍生物，以及基于 1,4-二氢吡啶的非核苷酸抑制剂，如硝苯地平和尼莫地平。所有这些配体都结合在 ODCase 的活性部位，表现出不同的相互作用，为设计针对这种有趣酶的新型抑制剂铺平了道路。我们提出了一个配体结构的经验模型，用于合理修饰新药设计和潜在的新先导结构。
