9b8m

Crystal structure of ornithine decarboxylase in complex with a novel inhibitor

spinqualitylabelsall models 9b8m, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9b8m is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.9Å Ligands: A1AQO, PLP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DCOR_HUMAN Publication Abstract from PubMed We here describe the design, synthesis, and biological activity of novel ornithine decarboxylase (ODC) inhibitors that show significantly higher potency in vitro than alpha-difluoromethylornithine (DFMO), a U.S. Food and Drug Administration (FDA) approved drug. We report two X-ray structures of ODC complexed with new ODC inhibitors, computational docking, molecular dynamics, and binding free energy calculations to validate the experimental models. The X-ray structures reveal that covalent adducts with pyridoxal phosphate (PLP) are formed in the active site of the human ODC enzyme, as verified by their preparation and enzymatic testing. Finally, we verified that the cellular activity of endogenous ODC was inhibited, and polyamine levels were reduced. Given that ODC is a clinically validated target, combined with the fact that DFMO is currently the only ODC inhibitor in clinical use for several indications, the further development of more potent ODC inhibitors with superior activity and physical properties is warranted. Design, Synthesis, and Biological Activity of Novel Ornithine Decarboxylase (ODC) Inhibitors.,Schultz CR, Aleiwi B, Zhou XE, Suino-Powell K, Melcher K, Almeida NMS, Wilson AK, Ellsworth EL, Bachmann AS J Med Chem. 2025 Mar 4. doi: 10.1021/acs.jmedchem.4c03120. PMID:40035393 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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