Discovery of Small Molecules that Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• Angiogenesis, the formation of new blood vessels, is crucial for cancer growth.
• Tyrosine kinases, particularly vascular endothelial growth factor receptor-2 (VEGFR-2), are key regulators of cancer angiogenesis.
• There is an urgent need for novel anti-angiogenic inhibitors targeting these pathways.

Purpose of the Study:

• To develop a structure-based pharmacophore model for VEGFR-2.
• To identify novel compounds with anti-angiogenic potential using the developed model.
• To validate the inhibitory capabilities of identified compounds through computational methods.

Main Methods:

• A structure-based pharmacophore model was built using VEGFR-2 (PDB code: 4AG8) complexed with axitinib.
• The model was used as a 3D query to retrieve candidate compounds.
• Molecular docking and molecular dynamics (MD) simulations using GROMACS were performed to assess binding affinity and stability.

Main Results:

• Seven candidate compounds were identified with higher dock scores than the reference compound.
• MD simulations confirmed stable binding modes and root mean square deviation for the compounds.
• The identified compounds maintained key interactions with critical VEGFR-2 residues (Glu885, Glu917, Cys919, Asp1046).

Conclusions:

• The seven identified compounds demonstrate potential as novel anti-angiogenic inhibitors.
• These compounds could serve as prototypes for designing and developing new cancer therapeutics.
• Targeting VEGFR-2 signaling pathways remains a promising strategy for cancer treatment.