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

## TL;DR

This study uses computer simulations to find promising cannabinoid compounds that may inhibit cancer-related proteins, focusing on their drug-like properties and potential for future testing.

## Contribution

The study identifies novel cannabinoid derivatives with favorable multi-target binding and pharmacokinetic profiles for EGFR and VEGFR proteins.

## Key findings

- Eight cannabinoid derivatives showed consistent inhibitory potential against EGFR, VEGFR-1, and VEGFR-2.
- Ajulemic Acid and 2′-Hydroxy-Delta (9)-THC exhibited favorable drug-like properties and predicted bioavailability.
- Glucuronidated THC metabolites had strong docking scores but poor drug-likeness, suggesting prodrug behavior.

## Abstract

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.