Identification of potential novel aromatase inhibitors as therapeutic strategies against breast cancer: insight into molecular docking, MD simulations and ADMET profiling.

BACKGROUND: Breast cancer remains a leading cause of morbidity and mortality in women worldwide. Reports show that overexpression of estrogen and estrogen receptors is a key driver of many breast cancers, and aromatase (CYP19A1) plays a central role in estrogen biosynthesis. Existing aromatase inhibitors such as Letrozole, androstenedione etc., often have side effects and drug resistance issues, hence there is a need for novel inhibitors with improved safety. METHODS: We retrieved 72 phytochemical compounds from Ricinus communis and compared them against Letrozole via structure-based in silico screening. Ligands were docked to aromatase (PDB ID: 3EQM) using AutoDock Vina in PyRx. Top hits were evaluated for drug-likeness via Lipinski's rule, and pharmacokinetic/toxicity parameters using SwissADME, admetSAR 2.0, and pkCSM. The binding modes were visualized, and molecular dynamics (MD) simulations (100 ns) with GROMACS were performed to assess stability, complemented by analyses of RMSD, RMSF, radius of gyration, and hydrogen bonds. RESULTS: Of the 72 compounds screened, 10 exhibited more negative docking scores than Letrozole's - 8.3 kcal/mol. Three compounds, including Stigmasterol (- 10.5 kcal/mol), Fucosterol (- 10.2 kcal/mol), and 7-oxo-β-sitosterol (≈ - 9.3 kcal/mol) were selected as top hits. These compounds formed favorable hydrophobic and hydrogen bonding interactions with key active site residues (including MET374, ALA306, TRP224). All three satisfy Lipinski's criteria and showed favorable ADMET profiles (good absorption, non-carcinogenic, minimal predicted CYP-inhibition). MD trajectories indicated that the complexes remain stable over 100 ns, with RMSD fluctuations within acceptable ranges and consistent hydrogen bonding. CONCLUSION: The three phytochemicals identified from Ricinus communis show promise as novel aromatase inhibitors with superior binding and favorable pharmacokinetic predictions compared to Letrozole. These compounds warrant further in vitro and in vivo study as potential breast cancer therapeutics.