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

Area of Science:

• Oncology
• Molecular Biology
• Computational Chemistry

Background:

• Angiogenesis is crucial for tumor growth, survival, and metastasis, supplying oxygen and nutrients.
• Tumor cells hijack angiogenesis through dysregulated signaling pathways, notably involving VEGFR-2 and mutant K-RAS G12C.
• VEGFR-2 and K-RAS G12C are critical mediators in tumor progression, presenting therapeutic targets.

Purpose of the Study:

• To identify novel dual inhibitors targeting both VEGFR-2 and K-RAS G12C.
• To discover compounds with potential anticancer and antiangiogenic properties.
• To explore new therapeutic strategies for cancer treatment.

Main Methods:

• In silico hybrid and hierarchical virtual screening of the NCI database.
• ADME filtering and ligand-based Biotarget Predictor Tool (BPT) analysis.
• Structure-based molecular docking and molecular dynamics simulations on VEGFR-2 and K-RAS G12C.

Main Results:

• A refined dataset of potential inhibitors was generated through virtual screening.
• Molecular docking identified promising small molecules interacting with both VEGFR-2 and K-RAS G12C.
• Compound 737734 demonstrated high stability in complex with both targets.

Conclusions:

• Compound 737734 is a promising dual-target inhibitor candidate for cancer therapy.
• The identified compound exhibits potential anticancer and antiangiogenic effects.
• This study highlights the efficacy of in silico screening for novel drug discovery.