Universidade Federal da Bahia, Faculdade de Farmácia, R. Barão de Jeremoabo, Salvador-BA, Brazil.
Bioorg Med Chem. 2010 Feb 15;18(4):1421-7. doi: 10.1016/j.bmc.2010.01.022. Epub 2010 Jan 18.
Selectivity plays a crucial role in the design of enzyme inhibitors as novel antiparasitic agents, particularly in cases where the target enzyme is also present in the human host. Purine nucleoside phosphorylase from Schistosoma mansoni (SmPNP) is an attractive target for the discovery of potential antischistosomal agents. In the present work, kinetic studies were carried out in order to determine the inhibitory potency, mode of action and enzyme selectivity of a series of inhibitors of SmPNP. In addition, crystallographic studies provided important structural insights for rational inhibitor design, revealing consistent structural differences in the binding mode of the inhibitors in the active sites of the SmPNP and human PNP (HsPNP) structures. The molecular information gathered in this work should be useful for future medicinal chemistry efforts in the design of new inhibitors of SmPNP having increased affinity and selectivity.
选择性在设计新型抗寄生虫药物的酶抑制剂中起着至关重要的作用，特别是在靶酶也存在于人类宿主中的情况下。曼氏血吸虫嘌呤核苷磷酸化酶（SmPNP）是发现潜在抗血吸虫药物的有吸引力的靶标。在本工作中，进行了动力学研究，以确定一系列 SmPNP 抑制剂的抑制效力、作用模式和酶选择性。此外，晶体学研究为合理的抑制剂设计提供了重要的结构见解，揭示了抑制剂在 SmPNP 和人 PNP（HsPNP）结构的活性部位结合模式中的一致结构差异。本工作中收集的分子信息对于未来在设计具有更高亲和力和选择性的 SmPNP 新抑制剂的药物化学研究应该是有用的。
