A Hybrid In Silico Approach for Identifying Dual VEGFR/RAS Inhibitors as Potential Anticancer and Anti-Angiogenic Agents

Abstract

: Background: Angiogenesis, the physiological process by which new blood vessels originate from pre-existing ones, can be triggered by tumor cells to promote the growth, survival, and progression of cancer. Malignant tumors require a constant blood supply to meet their needs for oxygen and nutrients, making angiogenesis a key process in tumor development. Its pathologic role is caused by the dysregulation of signaling pathways, particularly those involving VEGFR-2, a key mediator of angiogenesis, and the K-RAS G12C mutant, a promoter of VEGF expression. Given their critical involvement in tumor progression, these targets represent promising candidates for new cancer therapies. Methods and Results: In this study, we applied an in silico hybrid and hierarchical virtual screening approach to identify potential dual VEGFR-2/K-RAS G12C inhibitors with anticancer and antiangiogenic properties. To this end, we screened the National Cancer Institute (NCI) database through ADME filtering tools. The refined dataset was then submitted to the ligand-based Biotarget Predictor Tool (BPT) in a multitarget mode. Subsequently, structure-based analysis, including molecular docking studies on VEGFR and K-RAS G12C, was performed to investigate the interactions of the most promising small molecules with both targets. Conclusions: Finally, the molecular dynamics simulations suggested compound 737734 as a promising small molecule with high stability in complex with both VEGFR-2 and K-RAS G12C, highlighting its potential as a dual-target inhibitor for cancer therapy.