In Silico Molecular Docking and Pharmacokinetic Evaluation of Cannabinoid Derivatives as Multi-Target Inhibitors for EGFR, VEGFR-1, and VEGFR-2 Proteins

Cancer therapy development increasingly focuses on multi-target approaches to inhibit key proteins involved in tumor growth and angiogenesis. This study explored the potential inhibitory interactions of 110 cannabinoid derivatives using molecular docking simulations against epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor-1 (VEGFR-1), and VEGFR-2. Blind docking with AutoDock Vina identified eight recurrent hits across all three targets, including polar THC glucuronides and more drug-like cannabinoid scaffolds. Among these, 2′-Hydroxy-Delta (9)-THC and Ajulemic Acid combined favorable multi-target binding with superior predicted pharmacokinetic properties compared with other cannabinoids and reference inhibitors (lapatinib, motesanib, and sorafenib). ADME predictions highlighted Ajulemic Acid as the most promising oral candidate, showing optimal molecular weight, high oral bioavailability, and good gastrointestinal absorption, while 2′-Hydroxy-Delta (9)-THC exhibited potential for central nervous system exposure due to predicted blood–brain barrier permeability. In contrast, glucuronidated THC metabolites and highly lipophilic cannabinol esters displayed strong docking scores but suboptimal drug-likeness, suggesting prodrug- or metabolite-like behavior rather than suitability as primary oral leads. Toxicity predictions classified all compounds as moderately toxic, with Ajulemic Acid showing a comparatively more favorable safety profile. These findings do not demonstrate biological inhibition and should be interpreted strictly as hypothesis-generating computational evidence, providing a rational framework for future in vivo and in vitro validations.