Discovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors.
Lindsey G DeRattE Christine PietschJustin S CisarEdgar JacobyFaraz KazmiRosalie MaticoPaul ShafferAlexandra TannerWeixue WangRicardo AttarJames P EdwardsScott D KudukPublished in: ACS medicinal chemistry letters (2024)
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.
Keyphrases
- acute myeloid leukemia
- cell proliferation
- high throughput
- bioinformatics analysis
- small molecule
- oxidative stress
- dna binding
- white matter
- cell cycle
- single cell
- binding protein
- emergency department
- resting state
- genome wide
- stem cells
- gene expression
- anti inflammatory
- signaling pathway
- adverse drug
- bone marrow
- acute lymphoblastic leukemia
- climate change
- drug induced
- blood brain barrier