Structure-Based Design, Synthesis, and Characterization of Inhibitors of Human and Plasmodium falciparum Dihydroorotate Dehydrogenases
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- 作者：Matthew Davies ; Timo Heikkil ; Glenn A. McConkey ; Colin W. G. Fishwick ; Mark R. Parsons ; A. Peter Johnson
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：May 14, 2009
- 年：2009
- 卷：52
- 期：9
- 页码：2683-2693
- 全文大小：561K
- 年卷期：v.52,no.9(May 14, 2009)
- ISSN：1520-4804
文摘
Pyrimidine biosynthesis is an attractive drug target in a variety of organisms, including humans and the malaria parasite Plasmodium falciparum. Dihydroorotate dehydrogenase, an enzyme catalyzing the only redox reaction of the pyrimidine biosynthesis pathway, is a well-characterized target for chemotherapeutical intervention. In this study, we have applied SPROUT-LeadOpt, a software package for structure-based drug discovery and lead optimization, to improve the binding of the active metabolite of the anti-inflammatory drug leflunomide to the target cavities of the P. falciparum and human dihydroorotate dehydrogenases. Following synthesis of a library of compounds based upon the SPROUT-optimized molecular scaffolds, a series of inhibitors generally showing good inhibitory activity was obtained, in keeping with the SPROUT-LeadOpt predictions. Furthermore, cocrystal structures of five of these SPROUT-designed inhibitors bound in the ubiquinone binding cavity of the human dihydroorotate dehydrogenase are also analyzed.