Pharmacophore modeling,virtual screening,docking and in silico ADMET analysis of protein kinase B (PKB β) inhibitors |
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| Affiliation: | 1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China;2. College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China;3. Green Center for Systems Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, United States;4. Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China;1. Department of Biology, College of Science, University of Hail, PO Box 2440, Hail, Saudi Arabia;2. Molecular Diagnostic and Personalized Therapeutics Unit, University of Ha''il, Ha''il 2440, Saudi Arabia;3. Section of Histology-Cytology, Medicine Faculty of Tunis, University of Tunis El Manar, La Rabta-Tunis 1017, Tunisia;4. Laboratory of Histo-Embryology & Cytogenetics, Medicine Faculty of Sfax, University of Sfax, Sfax 3029, Tunisia;5. Department of Biotechnology, Parul Institute of Applied Sciences and Centre of Research for Development, Parul University, Vadodara 391760, Gujarat, India;6. Department of Chemistry, College of Science, University of Ha''il, PO Box 2440, Ha''il 81441, Saudi Arabia;7. Department of Marine Chemistry, Faculty of Marine Sciences, King Abdulaziz University, PO Box 80207, Jeddah 21589, Saudi Arabia;8. Botany & Microbiology Department, College of Sciences, King Saud University, Saudi Arabia;9. Laboratory of Genetics, Biodiversity and Valorisation of Bioressources, High Institute of Biotechnology-University of Monastir, Monastir 5000, Tunisia |
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| 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 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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