9B8M

Crystal structure of ornithine decarboxylase in complex with a novel inhibitor

これはPDB形式変換不可エントリーです。

9B8M の概要

• エントリーDOI: 10.2210/pdb9b8m/pdb
• 分子名称: Ornithine decarboxylase, O-{[(3R)-pyrrolidin-3-yl]methyl}hydroxylamine, PYRIDOXAL-5'-PHOSPHATE, ... (4 entities in total)
• 機能のキーワード: analogs, drug inhibitors, dfmo, carbohydrate
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 94785.44

構造登録者

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. (登録日: 2024-03-31, 公開日: 2025-03-12, 最終更新日: 2025-03-26)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.9 Å)