Background: Kinase domain of VEGFR-2 displays conformational flexibility which leads
to existence of two kinds of inhibitors viz. type I and type II inhibitors. They exhibit different binding
modes and this necessitates the development of separate pharmacophore models for them.
Methods: The virtual screening study for discovery of type I inhibitors of VEGFR-2 kinase was done
by using combined pharmacophore (generated using PHASE and validated by 3D-QSAR) and docking
(Glide) based approach. Validated pharmacophore was used as preliminary filter followed by
docking. ADME properties were predicted for retrieved hits using QikProp.
Results: ADHRR.94 with statistical parameters r2
test 0.94, r2
training 0.99, SD 0.0766, r2 0.9861, F 283.3,
RMSE 0.2605, q2 0.8115 and Pearson’s R 0.9723was identified as the best pharmacophore hypothesis
for type I inhibitors of VEGFR-2 kinase. Virtual screening study was done for Asinex Elite Libraries
comprising of 104400 molecules using ADHRR.94, HTVS docking and XP docking that resulted in
twelve hits. Asinex ligand 5686 with docking score of -10.48kcal/mol was top-ranking hit. It made
two hydrogen bonding interactions with Cys 919, one as an acceptor and other as a donor, which are
characteristic of type I inhibitors. Additional interactions observed were π-cation with Lys 868 and π-
πstacking with Phe 1047.Twelve hits had acceptable values for ADME properties.
Conclusion: Twelve hits with best obtained docking scores ranging from -10.48 to -7.23 kcal/mol and
mimicking characteristic type I inhibitor interactions were identified which could be probable inhibitors