Assessment of Annona muricata Phytochemicals as 17β-HSD1 Inhibitors through Molecular Docking, Dynamics Simulation, DFT, and ADMET Analyses
Abstract
Breast cancer remains a leading cause of female mortality, largely sustained by local oestrogen production. The enzyme 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is an enzyme involved in the oestrogen biosynthesis pathway, particularly in the conversion of estrone to estradiol, and is overexpressed in conditions such as breast cancer. Therefore, it is considered a relevant target for drug development. We evaluated phytocompounds from Annona muricata as prospective 17β-HSD1 inhibitors through an integrated in silico workflow. Twelve reported constituents (myristic acid, myrcene, palmitic acid, hexanoic acid, pentadecane, methyl 3-phenylpropionate, butyric acid, linalool, reticuline, phytol, camphene and calamenene) were geometry-optimised by density-functional theory, docked against 17β-HSD1 (PDB 3HB5), and screened for drug-likeness and ADMET liabilities. The top-ranked complexes-reticuline (ΔG_pred = -8.4 kcal mol-1) and calamenene (-7.7 kcal mol-1)-scored more favourably than the reference epirubicin (-5.7 kcal mol-1) and were subjected to 100 ns molecular-dynamics simulations. Both ligands remained stably anchored within the catalytic pocket, with root mean square deviation (RMSD) fluctuations below 2.0 Å, yet MM-PBSA binding free energies (reticuline -27 kJ mol-1; calamenene -9 kJ mol-1) did not surpass the reference. ADMET profiling predicted acceptable Caco-2 permeability (0.92-0.94), and only moderate hERG liability, but also signalled potential DILI and…
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