3.6. Molecular Modeling
Computer-aided drug design simulation could save the effort, time, and
resources required by traditional drug development methodology.
Molecular modeling was performed to comprehend the potential
interactions of the target compounds with VEGFR. Modulation activity of
pazopanib and sorafenib derivatives towards VEGFR receptor was detected
using glide docking of Schrodinger program. The docking study showed
that the docking profile of the target compounds were at the pazopanib
binding site (Fig. 6 ). Thys they are expected to have a similar
mode of action. The binding of Pazopanib to VEGFR in its inactive
conformation is believed to be similar to its interaction with its
originally recognized kinase target B-RAF, a component of the RAS signal
transduction network. Assuming so, the pyrimidine nitrogen in its
un-ionized form and the nearby aniline NH moiety H-bond with the amide
group of Cys919 in the hinge region (NH and carbonyl oxygen,
respectively). The benzimidazole moiety binds in a hydrophobic pocket,
possibly occupying the site normally reserved for Phe1047 in the
“DFG-in” (active) conformation. Compound 1 and Compound 2 were docked
well in Pazopanib biding site and set up many hydrogen bonds,
hydrophobic and electrostatic interaction (Fig. 6 ). CYS919,
PHE1046, GLU917, THR916, GLU885, PHE918, LUE840, ILE1044, ILE888,
ILE892, CYS1045 were the main amino acids involved in interactions.
Generally, quinazoline and triazine scaffold occupy a deep pocket of ATP
binding site and form hydrogen bond with the main amino acid involved in
phosphorylation processes, CYS919. Additionally, the two compounds could
form extra-hydrogen bonding with certain amino acids in hinge region
such as GLU917, GLU885, and THR916. While hydroxy-phenyl and
dichloro-phenyl were occupied in the hydrophobic pocket in DFG-in active
conformation forming hydrophobic and van der Wall interaction with PHE
1046, PHE918, LUE840, ILE1044, ILE888, ILE892, and CYS1045. Triazine
containing compound had highest docking score of -9.1 and glide emodel
of -62.6, while compound with quinazoline moiety showed -8.5 and -87.4
of docking score and glide emodel comparing to that of pazopanib, -9.5,
and -93.6.