Pharmacophore based 3D-QSAR modeling and free energy analysis of VEGFR-2 inhibitors.
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 (r(2) = 0.94 and q(2) = 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.
Centre for Bioinformatics, School of Life Sciences, Pondicherry University , R.V. Nagar, Kalapet, Puducherry , India.
Muthukumaran
M
Rajagopalan
Sangeetha
S
Balasubramanian
Amutha
A
Ramaswamy
Premendu Prakash
PP
Mathur
D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010091:Oximes / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D010091:Oximes; D014508:Urea; D040301:Vascular Endothelial Growth Factor Receptor-2