Discovery of novel CDK1 inhibitors by combining pharmacophore modeling, QSAR analysis and in silico screening followed by in vitro bioassay.

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Al-Sha'er MA, Taha MO

Discovery of novel CDK1 inhibitors by combining pharmacophore modeling, QSAR analysis and in silico screening followed by in vitro bioassay.

Eur J Med Chem. 2010 Sep;45(9):4316-30. doi: 10.1016/j.ejmech.2010.06.034. Epub 2010 Jun 30.

PubMed ID

20638755 [ View in PubMed

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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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Alvocidib	Cyclin-dependent kinase 1	IC 50 (nM)	30	N/A	N/A	Details