Pharmacophore and Docking Guided Virtual Screening Study for Discovery of Type I Inhibitors of VEGFR-2 Kinase

Abstract

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 of VEGFR-2.

Keywords: DFG-motif; VEGFR-2.; docking; pharmacophore; quantitative structure-activity relationship; type I inhibitor; virtual screening.