9N67

Crystal structure of dihydroorotate dehydrogenase from Leishmania braziliensis in complex with orotate

9N67 の概要

• エントリーDOI: 10.2210/pdb9n67/pdb
• 分子名称: Dihydroorotate dehydrogenase, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (6 entities in total)
• 機能のキーワード: lbdhodh, covalent, inhibitor, orotate, oxidoreductase
• 由来する生物種: Leishmania braziliensis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76688.99

構造登録者

Froes, T.Q.,Vaidergorn, M.M.,Emery, F.S.,Nonato, M.C. (登録日: 2025-02-05, 公開日: 2025-07-23, 最終更新日: 2025-10-08)

主引用文献

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., 68:18869-18884, 2025

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: 40658390
DOI: 10.1021/acs.jmedchem.5c00462

実験手法

X-RAY DIFFRACTION (1.8 Å)