Pharmacophore based 3D-QSAR modeling and free energy analysis of VEGFR-2 inhibitors

Abstract

VEGFR-2, a transmembrane tyrosine kinase receptor is responsible for angiogenesis and has been an attractive target in treating cancers. The inhibition mechanism of structurally diverse urea derivatives, reported as VEGFR-2 inhibitors, was explored by pharmacophore modeling, QSAR, and molecular dynamics based free energy analysis.The pharmacophore hypothesis AADRR, resulted in a highly significant atom based 3D-QSAR model (r² = 0.94 and q² = 0.84). Binding free energy analysis of the docked complexes of highly active and inactive compounds, after 7 ns MD simulation, revealed the importance of van der Waals interaction in VEGFR-2 inhibition. The decomposition of binding free energy on a per residue basis disclosed that the residues in hinge region and hydrophobic pocket play a role in discriminating the active and inactive inhibitors. Thus, the present study proposes a pharmacophore hypothesis representing the identified interactions pattern and its further application as a template in screening databases to identify novel VEGFR-2 inhibitor scaffolds.

Keywords::

• VEGFR-2
• Pharmacophore
• 3D-QSAR
• free energy analysis
• MMGBSA
• docking

Acknowledgement

The authors acknowledge the Centre for Excellence in Bioinformatics to conduct the research work. Sangeetha Balasubramanian, one of the authors, acknowledges the Department of Science and Technology, India for providing financial support through INSPIRE fellowship.

Declaration of interest

The authors report no declarations of interest.