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Structure-Based Design, Synthesis, and Characterization of Inhibitors of Human and Plasmodium falciparum Dihydroorotate Dehydrogenases

DOI: 10.1021/jm800963t DOI Help

Authors: Matthew Davies (School of Chemistry, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds) , Timo Heikkila (School of Chemistry, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds) , Glenn A. Mcconkey (School of Chemistry, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds) , Colin W. G. Fishwick (School of Chemistry, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds) , Mark R. Parsons (School of Chemistry, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds) , A. Peter Johnson (School of Chemistry, Faculty of Biological Sciences, and Astbury Centre for Structural Molecular Biology, University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 52 (9) , PAGES 2683 - 2693

State: Published (Approved)
Published: May 2009
Diamond Proposal Number(s): 6386

Abstract: 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.

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography