Computational screening of GC-MS-derived secondary metabolites from Botryodiplodia theobromae (Lasiodiplodia theobromae) as potential ERBIN inhibitors in breast cancer

Abstract
Background Botryodiplodia theobromae (syn. Lasiodiplodia theobromae) is an
endophytic fungus with a rich resource of bioactive secondary metabolites. Its
cytotoxicity towards BC cells has previously been studied. However, its mechanism
of action at a molecular level is still not well understood. This study was designed
to establish drug-likeness and binding affinity of GC-MS-detected B. theobromae
compounds against the ERBIN PDZ domain, a stabilizer of the HER2 receptor implicated
in the pathogenesis of Breast Cancer (BC).
Methods Fungal metabolites were extracted from B. theobromae using
dichloromethane and analysed by Gas Chromatography-Mass Spectrometry (GCMS)
to identify the compounds. The 2D and 3D structures of these compounds were
retrieved from PubChem and was evaluated for drug-likeness using Lipinski’s Rule of
Five. Molecular docking was conducted with AutoDock against the ERBIN protein (PDB
ID: 1MFG). LigPlot + was employed to visualize the key protein–ligand interactions for
the top-scoring compounds.
Results There were nine significant compounds identified through the application
of GC-MS. Analysis using Lipinski indicated that seven compounds were drug-like.
Molecular docking showed that [5-(4-Nitro-phenyl)- [1, 3, 4]oxadiazol-2-yl]-acetic
acid ethyl ester had the highest affinity of binding (–8.21 kcal/mol), followed by
1,2-Benzenedicarboxylic acid, mono[2-ethylhexyl] ester (–7.59 kcal/mol). LigPlot+
interaction diagrams confirmed the presence of favourable hydrogen bonds and
hydrophobic contacts with the ERBIN active site.
Conclusion This study emphasizes the promise of Botryodiplodia theobromae
secondary metabolites as ERBIN-mediated BC development inhibitors. The
combination of in vitro cytotoxic data and in silico molecular modelling is a good
starting point for future research on these fungal metabolites as new anticancer drugs