Assessment of <i>Annona muricata</i> Phytochemicals as 17β‐HSD1 Inhibitors through Molecular Docking, Dynamics Simulation, DFT, and ADMET Analyses

Abstract

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 carcinogenicity alerts that warrant caution. Reticuline and calamenene fulfilled all of Lipinski's criteria, with the exception of logP in the case of calamenene. Collectively, these findings nominate reticuline and calamenene as promising lead scaffolds for selective intracellular suppression of oestrogen biosynthesis. Experimental validation (enzyme kinetics, cell‐based assays and pharmacokinetic studies) is warranted to confirm their clinical potential in oestrogen‐dependent breast cancer.