Reis Renata A G, Calil Felipe Antunes, Feliciano Patricia Rosa, Pinheiro Matheus Pinto, Nonato M Cristina
Department of Chemistry, Georgia State University, Atlanta, GA 30302, United States.
Laboratório de Cristalografia de Proteínas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, 14040-903, Brazil.
Arch Biochem Biophys. 2017 Oct 15;632:175-191. doi: 10.1016/j.abb.2017.06.019. Epub 2017 Jun 27.
The flavoenzyme dihydroorotate dehydrogenase catalyzes the stereoselective oxidation of (S)-dihydroorotate to orotate in the fourth of the six conserved enzymatic reactions involved in the de novo pyrimidine biosynthetic pathway. Inhibition of pyrimidine metabolism by selectively targeting DHODHs has been exploited in the development of new therapies against cancer, immunological disorders, bacterial and viral infections, and parasitic diseases. Through a chronological narrative, this review summarizes the efforts of the scientific community to achieve our current understanding of structural and biochemical properties of DHODHs. It also attempts to describe the latest advances in medicinal chemistry for therapeutic development based on the selective inhibition of DHODH, including an overview of the experimental techniques used for ligand screening during the process of drug discovery.
黄素酶二氢乳清酸脱氢酶在从头嘧啶生物合成途径中六个保守酶促反应的第四步，催化（S）-二氢乳清酸立体选择性氧化为乳清酸。通过选择性靶向二氢乳清酸脱氢酶（DHODHs）来抑制嘧啶代谢，已被用于开发针对癌症、免疫紊乱、细菌和病毒感染以及寄生虫病的新疗法。通过按时间顺序叙述，本综述总结了科学界为实现我们目前对DHODHs结构和生化特性的理解所做的努力。它还试图描述基于DHODH选择性抑制的治疗开发中药物化学的最新进展，包括药物发现过程中用于配体筛选的实验技术概述。
