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.
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
Rotondo A.;Pellicane G.;
2025-01-01
Abstract
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.Pubblicazioni consigliate
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