3MHU

Crystal structure of dihydroorotate dehydrogenase from Leishmania major in complex with 5-Nitroorotic acid

Summary for 3MHU

• Entry DOI: 10.2210/pdb3mhu/pdb
• Related: 3C3N 3GYE
• Descriptor: Dihydroorotate dehydrogenase, FLAVIN MONONUCLEOTIDE, 5-nitro-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid, ... (6 entities in total)
• Functional Keywords: dihydroorotate dehydrogenase, pyrd, oxidoreductase
• Biological source: Leishmania major
• Total number of polymer chains: 2
• Total formula weight: 76552.85

Authors

Pinheiro, M.P.,Rocha, J.R.,Cheleski, J.,Montanari, C.A.,Nonato, M.C. (deposition date: 2010-04-08, release date: 2011-02-23, Last modification date: 2023-09-06)

Primary citation

Cheleski, J.,Rocha, J.R.,Pinheiro, M.P.,Wiggers, H.J.,da Silva, A.B.,Nonato, M.C.,Montanari, C.A.
Novel insights for dihydroorotate dehydrogenase class 1A inhibitors discovery.
Eur.J.Med.Chem., 45:5899-5909, 2010

PubMed Abstract: The enzyme dihydroorotate dehydrogenase (DHODH) has been suggested as a promising target for the design of trypanocidal agents. We report here the discovery of novel inhibitors of Trypanosoma cruzi DHODH identified by a combination of virtual screening and ITC methods. Monitoring of the enzymatic reaction in the presence of selected ligands together with structural information obtained from X-ray crystallography analysis have allowed the identification and validation of a novel site of interaction (S2 site). This has provided important structural insights for the rational design of T. cruzi and Leishmania major DHODH inhibitors. The most potent compound (1) in the investigated series inhibits TcDHODH enzyme with Kiapp value of 19.28 μM and possesses a ligand efficiency of 0.54 kcal mol(-1) per non-H atom. The compounds described in this work are promising hits for further development.

PubMed: 20965617
DOI: 10.1016/j.ejmech.2010.09.055

Experimental method

X-RAY DIFFRACTION (1.85 Å)