Molecular docking assessment of sesquiterpene lactones from Saussurea lappa as potential anti-melanoma agents

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.‎