# Integrated Computational Investigation of Cannabis sativa Phytoconstituents as Putative Multi-Target Inhibitors in Skin Cancer: A Molecular Docking, Dynamics, and ADMET Profiling Study

## TL;DR

This study explores how compounds from Cannabis sativa may inhibit key cancer pathways in skin cancer through computational methods.

## Contribution

The study identifies Cannabis sativa phytoconstituents as potential multitarget inhibitors for skin cancer signaling pathways.

## Key findings

- Several Cannabis sativa compounds showed strong binding affinities to EGFR, BRAF V600E, and TGF-β receptors.
- Molecular dynamics simulations confirmed stable protein-ligand interactions and favorable binding energetics.
- The compounds demonstrated good pharmacokinetic profiles and acceptable safety characteristics.

## Abstract

Background: Skin cancer progression is driven by the dysregulation of key oncogenic signaling pathways, including EGFR, BRAF V600E, and TGF-β, which collectively promote tumor proliferation, invasion, and metastatic progression. Targeting these pathways using multitarget natural modulators represents a promising therapeutic strategy. Methods: In this study, forty-nine phytoconstituents from Cannabis sativa were evaluated using an integrated computational approach to explore their inhibitory potential against EGFR, BRAF V600E, and the TGF-β receptor. Molecular docking was performed to assess binding affinities and interaction profiles, followed by ADMET analysis to evaluate pharmacokinetic and safety properties. The top-ranked compounds were further investigated using 200 ns molecular dynamics simulations and MM-GBSA binding free energy calculations to assess the stability and strength of protein–ligand interactions. Results: Several phytoconstituents exhibited strong binding affinities toward the target proteins, formed stable interactions with key active-site residues, and demonstrated favorable pharmacokinetic profiles with acceptable safety characteristics. Molecular dynamics simulations confirmed the structural stability of the selected protein–ligand complexes, while MM-GBSA analysis supported their favorable binding energetics. Conclusions: These findings suggest that Cannabis sativa phytoconstituents may represent a promising source of multitarget modulators capable of attenuating EGFR, BRAF V600E, and TGF-β driven oncogenic signaling in skin cancer. This study provides a mechanistic framework that supports further in vitro validation and the development of cannabis-derived therapeutic candidates for targeted skin cancer management.