Abstract:
Melanoma, a deadly skin cancer, is increasing in global incidence. The MAPK pathway,
frequently mutated in BRAF and NRAS genes, plays a central role in melanoma progression.
Although targeted therapies against this pathway have shown promise, resistance often
emerges, which necessitates the exploration of novel agents.
The in silico molecular docking method and ADME prediction were used to test nine natural
compounds, sesquiterpene lactones, from the medicinal plant Saussurea lappa for their
potential as melanoma key pathway inhibitors (NRAS, BRAF, and ERK2).
Lappadilactone had the strongest binding affinity, especially to ERK2 equal to -9.5 kcal/mol,
outperforming the reference ligand 8XE in binding energy. It formed stabilising interactions
within the active site, such as hydrogen bonds and hydrophobic contacts. Dehydrocostus
lactone demonstrated significant binding to both BRAF and ERK2 with binding energy of -
8.9 kcal/mol and -8.5 kcal/mol, respectively.
ADME predictions showed that the compounds had favourable physicochemical properties,
moderate lipophilicity, and high predicted gastrointestinal absorption.
These findings suggest that sesquiterpene lactones from Saussurea lappa, particularly
Lappadilactone and Dehydrocostus lactone, represent promising natural-based MAPK
pathway inhibitors with the potential to be novel targeted therapies against metastatic
melanoma.
