Discovery of Alternative Binding Poses through Fragment-Based Identification of DHODH Inhibitors.
ACS Med Chem Lett
; 15(3): 381-387, 2024 Mar 14.
Article
in En
| MEDLINE
| ID: mdl-38505861
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.
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Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
ACS Med Chem Lett
Year:
2024
Document type:
Article
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