Molecular Docking and Molecular Dynamics of Asiaticoside and Neoandrographolide as hDHFR Inhibitors for Breast Cancer Prevention

ABSTRACT Breast cancer is the most prevalent cancer among women worldwide and is often associated with the overexpression of nuclear receptors. Despite advances, effective treatments to curb breast cancer cell proliferation remain limited. Human dihydrofolate reductase (hDHFR) is a key enzyme in folate metabolism, and its inhibition leads to reduced tetrahydrofolate levels, impairing DNA synthesis and causing cell death. Methotrexate, a known hDHFR inhibitor, is effective but associated with adverse side effects. In this study, we employed molecular docking, ADMET prediction, and molecular dynamics (MD) simulations to identify novel hDHFR inhibitors. Fourteen plant‐derived compounds, identified through literature review, were evaluated for their binding affinity to hDHFR. Several compounds demonstrated stronger binding than methotrexate by interacting with key active‐site residues and showing favorable molecular orientations. Lipinski's rule and ADMET profiling were used to assess drug‐likeness and safety. Asiaticoside (PubChem CID: 11954171) and neoandrographolide, in particular, exhibited high binding affinity, favorable ADMET properties, and stability in MD simulations, suggesting strong interaction with the hDHFR active site and slight conformational effects on the enzyme. This study is the first to report asiaticoside and neoandrographolide as potential hDHFR inhibitors, highlighting their promise for further development in breast cancer therapy.