title: Discovery of novel CDK1 inhibitors by combining pharmacophore modeling, QSAR analysis and in silico screening followed by in vitro bioassay.
abstract: Cyclin-dependent kinase 1 (CDK1) is a valid anticancer target. With this in mind we applied a modeling workflow by combining pharmacophore modeling and QSAR analysis followed by in silico screening towards the discovery of novel inhibitory CDK1 scaffolds. Virtual screening identified 10 low micromolar inhibitory leads: 8 from the National Caner Institute (NCI) list of compounds and 2 from our in house list of established drugs and agrochemicals. The most potent NCI hit illustrated anti-CDK1 IC(50) value of 0.83 microM, while the drug hit isoxsuprine illustrated anti-CDK1 IC(50) value of 2.9 microM and the agrochemical hit foramsulfuran showed IC(50) = 3.6 microM. These results demonstrate that our virtual screening protocol is able to identify novel anti-CDK1 leads for subsequent development into potential anticancer agents.
authors.affiliation: Drug Discovery Unit, Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Queen Rania St, Amman, Jordan.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Al-Sha'er
authors.forename: Mutasem O
authors.initials: MO
authors.lastname: Taha
mesh_terms: D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D019295:Computational Biology; D016208:Databases, Factual; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve; D013816:Thermodynamics
chemical_list: D047428:Protein Kinase Inhibitors; D016203:CDC2 Protein Kinase