9B8M

Crystal structure of ornithine decarboxylase in complex with a novel inhibitor

This is a non-PDB format compatible entry.

Summary for 9B8M

• Entry DOI: 10.2210/pdb9b8m/pdb
• Descriptor: Ornithine decarboxylase, O-{[(3R)-pyrrolidin-3-yl]methyl}hydroxylamine, PYRIDOXAL-5'-PHOSPHATE, ... (4 entities in total)
• Functional Keywords: analogs, drug inhibitors, dfmo, carbohydrate
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 94785.44

Authors

Schultz, C.R.,Aleiwi, B.,Zhou, X.E.,Suino-Powell, K.,Melcher, K.,Brunzelle, J.S.,Almeida, N.M.S.,Wilson, A.K.,Ellsworth, E.,Bachmann, A.S. (deposition date: 2024-03-31, release date: 2025-03-12, Last modification date: 2025-03-26)

Primary citation

Schultz, C.R.,Aleiwi, B.,Zhou, X.E.,Suino-Powell, K.,Melcher, K.,Almeida, N.M.S.,Wilson, A.K.,Ellsworth, E.L.,Bachmann, A.S.
Design, Synthesis, and Biological Activity of Novel Ornithine Decarboxylase (ODC) Inhibitors.
J.Med.Chem., 68:5760-5773, 2025

PubMed Abstract: We here describe the design, synthesis, and biological activity of novel ornithine decarboxylase (ODC) inhibitors that show significantly higher potency than α-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.

PubMed: 40035393
DOI: 10.1021/acs.jmedchem.4c03120

Experimental method

X-RAY DIFFRACTION (2.9 Å)