3F1Q

Human dihydroorotate dehydrogenase in complex with a leflunomide derivative inhibitor 1

Summary for 3F1Q

• Entry DOI: 10.2210/pdb3f1q/pdb
• Descriptor: Dihydroorotate dehydrogenase, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (7 entities in total)
• Functional Keywords: dihydroorotate dehydrogenase, leflunomide, fad, flavoprotein, membrane, mitochondrion, mitochondrion inner membrane, oxidoreductase, pyrimidine biosynthesis, transit peptide
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion inner membrane; Single-pass membrane protein: Q02127
• Total number of polymer chains: 1
• Total formula weight: 40963.45

Authors

Heikkila, T.,Davies, M.,McConkey, G.A.,Fishwick, C.W.G.,Parsons, M.R.,Johnson, A.P. (deposition date: 2008-10-28, release date: 2009-06-09, Last modification date: 2023-11-01)

Primary citation

Davies, M.,Heikkila, T.,McConkey, G.A.,Fishwick, C.W.G.,Parsons, M.R.,Johnson, A.P.
Structure-based design, synthesis, and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases
J.Med.Chem., 52:2683-2693, 2009

PubMed 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.

PubMed: 19351152
DOI: 10.1021/jm800963t

Experimental method

X-RAY DIFFRACTION (2 Å)