J Mol Graph Model. 2026 Apr 8;146:109403. doi: 10.1016/j.jmgm.2026.109403. Online ahead of print.
ABSTRACT
Ornithine decarboxylase (ODC) is a pyridoxal-5′-phosphate (PLP)-dependent enzyme that catalyzes the rate-limiting step of polyamine biosynthesis, a pathway closely linked to cell proliferation and cancer progression. Frequently upregulated in tumors through MYC activation, ODC is an attractive target for anticancer drug discovery. In this work, a library of 412 phytochemicals from 52 medicinal plants with documented anticancer properties was screened in silico for drug-likeness, pharmacokinetics, and binding affinity against the ODC homodimer. Of these, 130 compounds advanced to molecular docking and ADMET analysis, yielding 13 top candidates with favorable affinity. Molecular dynamics (MD) simulations over 100 ns confirmed stable interactions for nine compounds, while MM-PBSA free energy and per-residue decomposition analysis identified five phytochemicals with favorable binding. Notably, Withanone, Withaferin A, and Withanolide D (Ashwagandha), Arjunic Acid (Haritaki), and Digitoxigenin (Tilpushpi) demonstrated higher affinity than the natural inhibitor Myricetin. These ligands engaged critical active-site residues and showed stable binding supported by RMSD, Radius of gyration, hydrogen bond persistence, PCA, and FEL analysis. Furthermore, statistical analysis of binding free energies and three independent 100 ns MD simulations for the two best-performing inhibitors were performed and compared with the reference compound which, confirmed the reproducibility and reliability of the binding results. The study is based on an established CADD approach with a significantly large library of natural compounds to screen specific ligands for the potential inhibition of the ODC. Furthermore, it revealed that water-mediated interaction and PLP-cofactor-associated binding mechanism stabilizes the ODC catalytic pocket. Overall, these results highlight selected phytochemicals as promising potential reversible ODC inhibitors, warranting experimental validation to establish their therapeutic potential in cancer treatment.
PMID:41965992 | DOI:10.1016/j.jmgm.2026.109403
