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

• Published in: Journal of medicinal chemistry 2009-05, Vol.52 (9), p.2683-2693
• Main Authors: Davies, Matthew, Heikkilä, Timo, McConkey, Glenn A, Fishwick, Colin W. G, Parsons, Mark R, Johnson, A. Peter
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Binding Sites; Biological and medical sciences; Crystallography, X-Ray; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Humans; Inhibitory Concentration 50; Medical sciences; Models, Molecular; Molecular Conformation; Oxidoreductases Acting on CH-CH Group Donors - antagonists & inhibitors; Oxidoreductases Acting on CH-CH Group Donors - chemistry; Oxidoreductases Acting on CH-CH Group Donors - metabolism; Pharmacology. Drug treatments; Plasmodium falciparum - enzymology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800963t

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.