Pharmacophore modeling, virtual screening, docking and in silico ADMET analysis of protein kinase B (PKB β) inhibitors

Protein kinase B (PKB) is a key mediator of proliferation and survival pathways that are critical for cancer growth. Therefore, inhibitors of PKB are useful agents for the treatment of cancer. Herein, we describe pharmacophore-based virtual screening combined with docking study as a rational strategy for identification of novel hits or leads. Pharmacophore models of PKB β inhibitors were established using the DISCOtech and refined with GASP from compounds with IC50 values ranging from 2.2 to 246 nM. The best pharmacophore model consists of one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD) site and two hydrophobic (HY) features. The pharmacophore models were validated through receiver operating characteristic (ROC) and Güner-Henry (GH) scoring methods indicated that the model-3 was statistically valuable and reliable in identifying PKB β inhibitors. Pharmacophore model as a 3D search query was searched against NCI database. Several compounds with different structures (scaffolds) were retrieved as hits. Molecules with a Qfit value of more than 95 and three other known inhibitors were docked in the active site of PKB to further explore the binding mode of these compounds. Finally in silico pharmacokinetic and toxicities were predicted for active hit molecules. The hits reported here showed good potential to be PKB β inhibitors.

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► Pharmacophore models of PKB β inhibitors were established by using the DISCOtech and GASP.
► The pharmacophore models were validated through ROC and GH scoring methods.
► Pharmacophore model as a 3D search query was searched against NCI database.
► Molecules with a Qfit value more than 95 along with known inhibitors were docked in PKB.
► In silico pharmacokinetic and toxicities were predicted for best docked hit molecules.
► Reported hits showed good potential to be PKB β inhibitors.