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Assessment of Annona muricata Phytochemicals as 17β-HSD1 Inhibitors through Molecular Docking, Dynamics Simulation,
Emad Rashad Sindi1, Md Jannatul Islam Polash2, Guilherme Bastos Alves3
1Division of Clinical Biochemistry, Department of Basic Medical Sciences, College of Medicine, University of Jeddah, Jeddah, Saudi Arabia.
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.
Insights
Phytocompounds from Annona muricata, specifically reticuline and calamenene, show potential as 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) inhibitors. These compounds may offer a new strategy for treating oestrogen-dependent breast cancer by suppressing oestrogen biosynthesis.
Area of Science:
- Medicinal Chemistry
- Computational Biology
- Pharmacology
Background:
- Breast cancer mortality is high, often driven by local oestrogen production.
- 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is crucial for oestrogen biosynthesis and is overexpressed in breast cancer, making it a key drug target.
Purpose of the Study:
- To investigate phytocompounds from Annona muricata as potential inhibitors of 17β-HSD1.
- To evaluate the drug-likeness and ADMET properties of these compounds using computational methods.
Main Methods:
- In silico screening of twelve Annona muricata constituents against 17β-HSD1.
- Geometry optimization using density-functional theory and molecular docking.
- Molecular dynamics simulations and MM-PBSA binding free energy calculations.
- ADMET profiling and Lipinski's rule-of-five analysis.
Main Results:
- Reticuline and calamenene demonstrated strong binding affinities to 17β-HSD1, outperforming the reference drug epirubicin in initial docking.
- Molecular dynamics simulations confirmed stable binding of reticuline and calamenene within the enzyme's catalytic pocket.
- ADMET profiling indicated acceptable Caco-2 permeability and moderate hERG liability, but also raised concerns regarding potential DILI and carcinogenicity.
Conclusions:
- Reticuline and calamenene are identified as promising lead scaffolds for selective intracellular suppression of oestrogen biosynthesis.
- Further experimental validation, including enzyme kinetics and cell-based assays, is necessary to confirm their therapeutic potential for oestrogen-dependent breast cancer.
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