Screening of 60,544 Traditional Chinese Medicine (TCM) compounds against the most oncogenic K-Ras(G12D) mutation switch-I/II allosteric pocket: a comprehensive structure-based screening and pharmacokinetics evaluation

Cancer remains a major global health issue, with particular difficulties in treating cancers associated with mutations. The K-Ras (G12D) mutation, a common oncogenic variant, is linked to aggressive forms of different cancers such as pancreatic ductal adenocarcinoma, non-small cell lung cancer, and colorectal cancer. This study investigates the potential of Traditional Chinese Medicine (TCM) compounds to target K-Ras(G12D) allosteric pockets. We screened a large library of TCM compounds, molecular docking, molecular dynamic (MD) simulations, and thermodynamic binding free energy calculations were performed and the compounds that outperform the reference drug, TH-Z835, were selected for further in-depth analysis. Among these, 10-hydroxycamptothecin, hypecorinine, and dehydroevodiamine showed highly promising activity with a diverse range of binding forces and interactions. This comprehensive screening study, albeit predictive, would offer a foundation for further experimental investigation and the development of new therapeutic approaches that leverage TCM compounds to tackle different cancers.