Investigating the molecular mechanisms of phytochemicals targeting Ras-related C3 botulinum toxin substrate 1 (Rac1) to inhibit breast cancer metastasis via endoplasmic reticulum stress and Wnt-PCP signaling pathway.

CONTEXT: Breast cancer metastasis remains a significant challenge in oncology, necessitating novel therapeutic approaches. Rac1 is a small GTPase involved in Wnt-planar cell polarity (Wnt-PCP) signaling and modulation of endoplasmic reticulum (ER) stress, and it has emerged as a promising target for inhibiting cancer progression. This study investigates the potential of cinnamaldehyde, a bioactive compound derived from cinnamon bark, as a potential Rac1 inhibitor. Computational analyses reveal that cinnamaldehyde exhibits higher binding specificity and efficacy to Rac1 than a reference inhibitor. Molecular dynamics (MD) simulations, essential dynamics, and MM-PBSA further confirm its stable binding with minimal impact on Rac1's structural conformation, which supports its potential as a lead compound for breast cancer therapy.

METHODS: A molecular docking study was performed using InstaDock and AutoDock Tools to assess cinnamaldehyde's binding affinity for Rac1. Pharmacokinetic properties were evaluated through SwissADME, and the PASS online tool was used for activity prediction. Protein-ligand interaction analyses were conducted using Discovery Studio Visualizer. All-atom MD simulations were performed for 500 ns using the GROMACS 2022 package with the CHARMM36 force field to analyze the stability of the cinnamaldehyde-Rac1 complex. The binding free energy computations were performed using the MM-PBSA approach.