Dual targeting of IGF-1R and K-RAS with natural phytochemicals for lung cancer therapy: an in-silico study

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, and the limitations and adverse effects of conventional chemotherapy necessitate the exploration of alternative therapeutic strategies. In this study, we used in-silico methods to identify bioactive compounds from medicinal plants with potential anti-lung cancer activity. We aimed to find potential inhibitors for the prevention of lung cancer, which can target two important proteins-insulin-like growth factor receptor (IGF-1R) and Kirsten rat sarcoma viral oncogene homologue (KRAS). A library of 1584 phytochemicals derived from 12 medicinal plants was retrieved from the IMPPAT 2.0 database and virtually screened using PyRx 0.8 software. According to the results, 17Beta-Hydroxywithanolide K and Ginkgolide A demonstrated strong binding affinity to IGF-1R (-9.4 Kcal/mol) and KRAS (-6.9 Kcal/mol), respectively, compared to the synthetic inhibitors Picropodophyllin (-7.7 Kcal/mol) and Sotorasib (-5.9 Kcal/mol). Pharmacokinetic (ADME) and toxicity analysis indicated favorable characteristics, including high gastrointestinal absorption and non-toxicity. Molecular dynamics (MD) simulations of 100 ns duration confirmed the stability of the protein-ligand complex. Overall, 17Beta-Hydroxywithanolide K and Ginkgolide A have potential as natural therapeutic agents for the treatment of lung cancer. However, additional in vitro and in vivo experiments are needed to validate these computational results.