Cancer is a leading cause of global death. Medicinal plants have gained increasing attention in cancer drug discovery. In this study, the stem bark extract of Olax subscorpioidea, which is used in ethnomedicine to treat cancer, was subjected to phytochemical investigation leading to the isolation of oleanolic acid (OA). The structure was elucidated by 1-dimensional and 2-dimensional nuclear magnetic resonance spectroscopic (NMR) data, and by comparing its data with previously reported data. Molecular docking was used to investigate the interactions of OA with nine selected cancer-related protein targets. OA docked well with human 17β-hydroxysteroid dehydrogenase type-1 (17βHSD1), caspase-3, and epidermal growth factor receptor tyrosine kinase (binding affinities: -9.8, -9.3, and -9.1 kcal/mol, respectively). OA is a triterpenoid compound with structural similarity to steroids. This similarity with the substrates of 17βHSD1 gives the inhibitor candidate an excellent opportunity to bind to 17βHSD1. The structural and functional dynamics of OA-17βHSD1 were investigated by molecular dynamics simulations at 240 ns. Molecular mechanics/Poisson-Boltzmann surface area (MMPBSA) studies showed that OA had a binding free energy that is comparable with that of vincristine (-52.76, and -63.56 kcal/mol, respectively). The average C-α root mean square of deviation (RMSD) value of OA (1.69 Å) compared with the unbound protein (2.01 Å) indicated its high stability at the protein's active site. The binding energy and stability at the active site of 17βHSD1 recorded in this study indicate that OA exhibited profound inhibitory potential. OA could be a good scaffold for developing new anti-breast cancer drugs.
Keywords: 17β-hydroxysteroid dehydrogenase-1; Olax subscorpioidea; breast cancer; molecular docking; molecular dynamics simulations; nuclear magnetic resonance; oleanolic acid.
Oleanolic acid has been isolated from the cytotoxic fraction of Olax subscorpioidea stem back extract. Its structure was deduced by 1D- and 2D-NMR analyses.The compound has strong interaction with human 17β-hydroxysteroid dehydrogenase-1 (PDB: 1FDW), caspase-3 (PDB: 1GFW), epidermal growth factor receptor tyrosine kinase (PDB: 5JEB), and poly(ADP-ribose) polymerase-1 (PDB: 5DS3), with binding affinities of –9.8, –9.3, –9.1, and –8.9 kcal/mol, respectively.MMPBSA studies, C-α RMSD and other MD parameters supported the inhibitory potential of oleanolic acid against critical residues involved in the catalysis of 17β-hydroxysteroid dehydrogenase-1.