Kaempferols from Echinacea purpurea demonstrate anti-cancer potential by targeting anexelekto in breast cancer therapy using chemoinformatics approach.

BACKGROUND: Breast cancer is one of the most common cancer types among women, especially in developing and underdeveloped nations like Nigeria. Anexelekto (AXL) is one of the well-known proteins that is implicated in various cancer types, including breast cancer, and it remains one of the focuses of targeted therapy. However, several drugs have been identified as inhibitors of this oncogenic protein, but they often come with toxic concerns in addition to their unaffordability to people of low- or middle-income countries. Thus, there is a crucial need to identify pocket-friendly inhibitors with negligible side effects targeting AXL. Therefore, bioactive compounds from plants such as Echinacea purpurea may be a promising agent in this regard. OBJECTIVE: The study sought to investigate the potential of bioactive compounds derived from Echinacea purpurea to inhibit the AXL protein implicated in breast cancer. METHODS: Structural bioinformatics via molecular docking and density functional theory (DFT) analysis was utilised for the identification of novel AXL inhibitors from Echinacea purpurea bioactive compounds. The compounds were further subjected to pharmacokinetic and drug-likeness analysis. Results obtained from the compounds were compared against those of Foretinib, a known AXL inhibitor. Additionally, their complexes with AXL were subjected to a 100 ns molecular dynamics (MD) simulation analysis utilising the Desmond v2020-4 software in Schrödinger (Academic version) in a Linux environment. RESULTS: Among all favourable binding scores, Kaempferol-7-o-Neohesperidoside, Kaempferol 3-gentiobioside-7-rhamnoside, and Kaempferol 3-o-beta-d-glucopyranosyl-7-o-alpha-L-rhamnopyranoside showed the highest binding score of -9.2, -8.9, and - 8.6 Kcal/mol, respectively, compared to Foretinib (-8.1 Kcal/mol). Stigmasterol and β-sitosterol also showed a higher binding affinity and binding score of -8.4 and - 8.3 Kcal/mol, respectively, against the AXL compared to the standard drug. DFT analysis revealed that Kaempferol 3-o-beta-d-glucopyranosyl-7-o-alpha-L-rhamnopyranoside has the highest LUMO-HOMO gap of -4.354 eV, suggesting greater potential for electron donation and high drug-enzyme reactivity. Also, the pharmacokinetic profiling of the selected compounds is favourable. Findings from MD simulation showed that the protein-ligand complexes formed by these compounds maintained structural stability, compactness, and low atomic fluctuations throughout a 100-ns simulation period. CONCLUSION: In silico studies show that E. purpurea-derived compounds, especially Kaempferol 3-o-beta-d-glucopyranosyl-7-o-alpha-L-rhamnopyranoside, have better inhibitory potential against AXL and better pharmacokinetic profiles when compared with Foretinib. These compounds are thus proposed as novel AXL inhibitors for the treatment of breast cancer. Further, in vivo studies are needed to confirm the potency of the studied compounds.