9N67
Crystal structure of dihydroorotate dehydrogenase from Leishmania braziliensis in complex with orotate
Summary for 9N67
| Entry DOI | 10.2210/pdb9n67/pdb |
| Descriptor | Dihydroorotate dehydrogenase, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (6 entities in total) |
| Functional Keywords | lbdhodh, covalent, inhibitor, orotate, oxidoreductase |
| Biological source | Leishmania braziliensis |
| Total number of polymer chains | 2 |
| Total formula weight | 76688.99 |
| Authors | Froes, T.Q.,Vaidergorn, M.M.,Emery, F.S.,Nonato, M.C. (deposition date: 2025-02-05, release date: 2025-07-23, Last modification date: 2025-07-30) |
| Primary citation | Froes, T.Q.,Alegbejo Price, T.O.,Fleck Godoi, B.,Vaidergorn, M.M.,Dos Santos, T.,Leite, P.I.P.,Silva, D.G.,Dias da Purificacao, A.,Loch, L.,Schenkman, S.,Kratz, J.M.,da Silva Emery, F.,Nonato, M.C. Barbituric Acid Derivatives as Covalent Inhibitors of Leishmania braziliensis Dihydroorotate Dehydrogenase. J.Med.Chem., 2025 Cited by PubMed Abstract: Covalent drug design applied to parasite proteins enables selective therapies by targeting nucleophilic residues of macromolecules. We present the first covalent inhibitors of dihydroorotate dehydrogenase (DHODH), a key enzyme in pyrimidine biosynthesis with a reactive cysteine (Cys) in its active site. From barbituric acid derivatives, we discovered as a DHODH inhibitor with leishmanicidal activity, exhibiting an IC of 0.5 ± 0.1 μM, a K/K of 767 Ms, no inhibition of the human ortholog, and an EC of 11 ± 5 μM in promastigotes, with no cytotoxicity in THP-1 cells and good passive permeability. X-ray crystallography confirms covalent bond formation with Cys and reveals active-site rearrangements. These findings support the proposed covalent inhibition mechanism and provide structural insights for further optimization. Our study validates DHODH as a promising target for leishmaniasis therapy and highlights the potential of covalent inhibition in antiparasitic drug discovery. PubMed: 40658390DOI: 10.1021/acs.jmedchem.5c00462 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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