Investigation of the binding affinity of cinnamic acid derivatives against the breast cancer cell line MCF-7 through docking

Abstract

This study presents the rational design and computational evaluation of novel cinnamic acid–peptide conjugates as potential multi-target inhibitors for breast cancer therapy. Five conjugates (S1–S5) were synthesized in silico by coupling cinnamic acid with selected amino acid residues to enhance receptor affinity and pharmacokinetic behavior. Molecular docking was performed against estrogen receptor alpha (ERα) and human epidermal growth factor receptor 2 (HER2) to assess binding efficiency and interaction profiles. The results revealed that S2 (Lys–Tyr) and S3 (Arg–Trp) exhibited the strongest binding affinities (ΔG ≈ –9 kcal/mol) and sub-micromolar inhibition constants, supported by multi-type interactions including ionic contacts, hydrogen bonding, and π–π stacking. Comparative analysis demonstrated that conjugates containing charged and aromatic residues achieved superior receptor stabilization compared to amphiphilic analogs such as S5 (Ser–Leu).

ADMET profiling confirmed that S2 and S3 exhibit favorable absorption, solubility, and drug-likeness parameters, along with low predicted toxicity, which correlates well with their docking performance. The integrated structure–activity relationship (SAR) and ADMET evaluation highlight the translational potential of these hybrids as safe and effective lead compounds. Overall, the study establishes cinnamic acid–peptide conjugation as a promising strategy for developing multi-target breast cancer therapeutics, bridging natural product chemistry with peptide-based drug design.