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.

Type 2 Diabetes Mellitus and MASH are converging metabolic epidemics sharing interconnected pathophysiological mechanisms. GSK-3β, a master metabolic regulator whose sustained hyperactivation drives both diseases, represents an attractive dual therapeutic target. This study employed a comprehensive in silico workflow to identify natural product-derived GSK-3β inhibitors from the Natural Products Atlas. A total of 36,545 microbial natural products were screened for drug-likeness, followed by an E-pharmacophore model derived from the GSK-3β structure (PDB ID: 4ACC). The docking protocol was validated by re-docking and enrichment analysis. Lead compounds were further evaluated using MMGBSA binding free energy calculations, Induced Fit Docking (IFD), AutoQSAR, and ADMET predictions. The validated docking protocol reproduced the 7YG crystallographic pose (RMSD = 0.8357 Å) and showed exceptional discriminatory power (ROC = 0.98; AUC = 0.97; EF₅% = 100%). NPA011425, NPA014875, NPA020257, NPA004276, NPA034843, and NPA036064 exhibited XP docking scores from − 6.858 to − 11.059 kcal/mol, superior to the co-crystallized ligand (− 6.455 kcal/mol), AR-A014418 (− 5.929 kcal/mol), and Tideglusib (− 5.895 kcal/mol). NPA014875 showed the strongest binding free energy (− 62.67 kcal/mol), comparable to the native ligand (− 63.15 kcal/mol). IFD confirmed receptor-adaptive binding, and all hits formed key hydrogen bonds with conserved hinge-region residues (Asp133, Val135, Pro136) while engaging the hydrophobic ATP-binding pocket. NPA020257 displayed predicted potency (pIC50 = 6.82). All six hits complied with Lipinski’s rules and showed favorable pharmacokinetic profiles. NPA020257, NPA034843, and NPA036064 emerged as the most balanced candidates. These findings highlight microbial natural products as promising scaffolds for GSK-3β inhibitor development, warranting further molecular dynamics, enzymatic, and cellular validation.