PDBsum entry 5mvc

Oxidoreductase

PDB id: 5mvc

Contents

Protein chain

352 a.a.

Ligands

FMN

ORO

Y9B

ACT ×2

Metals

_CL ×5

Waters ×288

PDB id:

5mvc

Name:

Oxidoreductase

Title:

Crystal structure of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds

Structure:

Dihydroorotate dehydrogenase (quinone), mitochondrial. Chain: a. Synonym: dhodehase,dihydroorotate oxidase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dhodh. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

1.85Å R-factor: 0.163 R-free: 0.189

Authors:

P.Goyal,M.Andersson,A.C.Moritzer,S.Sainas,A.C.Pippione,D.Boschi,S.Al- Kadaraghi,M.Lolli,R.Friemann

Key ref:

S.Sainas et al. (2017). Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds. Eur J Med Chem, 129, 287-302. PubMed id: 28235702 DOI: 10.1016/j.ejmech.2017.02.017

Date:

16-Jan-17 Release date: 08-Mar-17

Protein chain

Q02127  (PYRD_HUMAN) -  Dihydroorotate dehydrogenase (quinone), mitochondrial from Homo sapiens

Seq: 395 a.a.

Struc: 352 a.a.

Enzyme reactions

• Enzyme class: E.C.1.3.5.2 - dihydroorotate dehydrogenase (quinone).
• Reaction: (S)-dihydroorotate + a quinone = orotate + a quinol

(S)-dihydroorotate (Bound ligand (Het Group name = ORO) corresponds exactly) + quinone = orotate + quinol

• Cofactor: FMN

FMN (Bound ligand (Het Group name = FMN) corresponds exactly)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.ejmech.2017.02.017

Eur J Med Chem 129:287-302 (2017)

PubMed id: 28235702

Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds.

S.Sainas, A.C.Pippione, M.Giorgis, E.Lupino, P.Goyal, C.Ramondetti, B.Buccinnà, M.Piccinini, R.C.Braga, C.H.Andrade, M.Andersson, A.C.Moritzer, R.Friemann, S.Mensa, S.Al-Kadaraghi, D.Boschi, M.L.Lolli.

ABSTRACT

A new generation of potent hDHODH inhibitors designed by a scaffold-hopping replacement of the quinolinecarboxylate moiety of brequinar, one of the most potent known hDHODH inhibitors, is presented here. Their general structure is characterized by a biphenyl moiety joined through an amide bridge with an acidic hydroxyazole scaffold (hydroxylated thiadiazole, pyrazole and triazole). Molecular modelling suggested that these structures should adopt a brequinar-like binding mode involving interactions with subsites 1, 2 and 4 of the hDHODH binding site. Initially, the inhibitory activity of the compounds was studied on recombinant hDHODH. The most potent compound of the series in the enzymatic assays was the thiadiazole analogue 4 (IC50 16 nM). The activity was found to be dependent on the fluoro substitution pattern at the biphenyl moiety as well as on the choice/substitution of the heterocyclic ring. Structure determination of hDHODH co-crystallized with one representative compound from each series (4, 5 and 6) confirmed the brequinar-like binding mode as suggested by modelling. The specificity of the observed effects of the compound series was tested in cell-based assays for antiproliferation activity using Jurkat cells and PHA-stimulated PBMC. These tests were also verified by addition of exogenous uridine to the culture medium. In particular, the triazole analogue 6 (IC50 against hDHODH: 45 nM) exerted potent in vitro antiproliferative and immunosuppressive activity without affecting cell survival.