An in silico molecular docking and simulation study to identify potential anticancer phytochemicals targeting the RAS signaling pathway

by Mahir Azmal, Jibon Kumar Paul, Fatema Sultana Prima, Omar Faruk Talukder, Ajit Ghosh

The dysregulation of the rat sarcoma (RAS) signaling pathway, particularly the MAPK/ERK cascade, is a hallmark of many cancers, leading to uncontrolled cellular proliferation and resistance to apoptosis-inducing treatments. Dysregulation of the MAPK/ERK pathway is common in various cancers including pancreatic, lung, and colon cancers, making it a critical target for therapeutic intervention. Natural compounds, especially phytochemicals, offer a promising avenue for developing new anticancer therapies due to their potential to interfere with these signaling pathways. This study investigates the potential of anticancer phytochemicals to inhibit the MAPK/ERK pathway through molecular docking and simulation techniques. A total of 26 phytochemicals were screened from an initial set of 340 phytochemicals which were retrieved from Dr. Duke’s database using in silico methods for their binding affinity and stability. Molecular docking was performed to identify key interactions with ERK2, followed by molecular dynamics (MD) simulations to evaluate the stability of these interactions. The study identified several phytochemicals, including luteolin, hispidulin, and isorhamnetin with a binding score of -10.1±0 Kcal/mol, -9.86±0.15 Kcal/mol, -9.76±0.025 Kcal/mol, respectively as promising inhibitors of the ERK2 protein. These compounds demonstrated significant binding affinities and stable interactions with ERK2 in MD simulation studies up to 200ns, particularly at the active site. The radius of gyration analysis confirmed the stability of these phytochemical-protein complexes’ compactness, indicating their potential to inhibit ERK activity. The stability and binding affinity of these compounds suggest that they can effectively inhibit ERK2 activity, potentially leading to more effective and less toxic cancer treatments. The findings underscore the therapeutic promise of these phytochemicals, which could serve as a basis for developing new cancer therapies.