8VHM

Structure of DHODH in Complex with Fragment 2

This is a non-PDB format compatible entry.

Summary for 8VHM

• Entry DOI: 10.2210/pdb8vhm/pdb
• Descriptor: Dihydroorotate dehydrogenase (quinone), mitochondrial, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (8 entities in total)
• Functional Keywords: dhodh, oxidoreductase, inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 41343.64

Authors

Shaffer, P.L. (deposition date: 2024-01-02, release date: 2024-04-03)

Primary citation

DeRatt, L.G.,Pietsch, E.C.,Cisar, J.S.,Jacoby, E.,Kazmi, F.,Matico, R.,Shaffer, P.,Tanner, A.,Wang, W.,Attar, R.,Edwards, J.P.,Kuduk, S.D.
Discovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors.
Acs Med.Chem.Lett., 15:381-387, 2024

PubMed Abstract: Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that affects many aspects essential to cell proliferation and survival. Recently, DHODH has been identified as a potential target for acute myeloid leukemia therapy. Herein, we describe the identification of potent DHODH inhibitors through a scaffold hopping approach emanating from a fragment screen followed by structure-based drug design to further improve the overall profile and reveal an unexpected novel binding mode. Additionally, these compounds had low P-gp efflux ratios, allowing for applications where exposure to the brain would be required.

PubMed: 38505861
DOI: 10.1021/acsmedchemlett.3c00543

Experimental method

X-RAY DIFFRACTION (2.26 Å)