title: Pharmacophore modeling, virtual screening, docking and in silico ADMET analysis of protein kinase B (PKB β) inhibitors.
abstract: 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 246nM. 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382 481, Gujarat, India. vicky_1744@yahoo.com
authors.forename: Vivek K
authors.initials: VK
authors.lastname: Vyas
authors.forename: Manjunath
authors.initials: M
authors.lastname: Ghate
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Goel
mesh_terms: D020134:Catalytic Domain; D049109:Cell Proliferation; D055808:Drug Discovery; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009369:Neoplasms; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D012372:ROC Curve; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt