biostudies-literatureUnknown15(3)DeRatt LGDihydroorotate 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.ACS medicinal chemistry letters381-387https://www.ebi.ac.uk/biostudies/studies/S-EPMC10945543biostudies-literatureDiscovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors.PMC10945543Pietsch ECJacoby EAttar REdwards JPKazmi FKuduk SDMatico RShaffer PDeRatt LGTanner AWang WCisar JSfalseDiscovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors.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.2024-01-01T00:00:00Z2024 Mar2026-06-02T18:06:34.785Z2025-04-04T00:26:27.039ZS-EPMC109455433850586110.1021/acsmedchemlett.3c00543