Exploring the Therapeutic Potential of Cannabidiol in Cutaneous Squamous Cell Carcinoma: An Integrated Computational and Experimental Study

ABSTRACT Cutaneous squamous cell carcinoma (cSCC) poses a significant therapeutic challenge due to its aggressive nature and recurrence rates. The current treatment 5‐fluorouracil (5‐FU) is associated with adverse skin reactions. This study investigates cannabidiol (CBD) as a potential alternative therapy for cSCC through an integrated computational and experimental approach. Density functional theory (DFT) using the M06‐2X/6‐31+G(d,p) basis set revealed that CBD's smaller HOMO–LUMO gap (0.282 eV) compared to 5‐FU (0.288 eV) indicates a higher reactivity and potential biological interactions. Cannabidiol exhibits a higher binding affinity toward the CB1 receptor (−9.986 kcal/mol) than 5‐FU (−3.760 kcal/mol). Molecular dynamics simulations demonstrate that the CBD–CB1 complex remains stable through hydrogen bonding and hydrophobic interactions. Binding free energy calculations (MM‐GBSA) further confirmed CBD's enhanced affinity (−69.696 kcal/mol) over 5‐FU (−28.241 kcal/mol). Experimentally, CBD exhibited greater cytotoxicity against A431 cSCC cells with an IC 50 of 2.76 μM compared to 5‐FU's IC 50 of 5.61 μM. These integrated findings suggest that CBD is a promising alternative therapeutic candidate for cSCC, offering superior cytotoxicity and stable molecular interactions compared to 5‐FU.