Virtual screening for Raf-1 kinase inhibitors based on pharmacophore model of substituted ureas.

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Li HF, Lu T, Zhu T, Jiang YJ, Rao SS, Hu LY, Xin BT, Chen YD

Virtual screening for Raf-1 kinase inhibitors based on pharmacophore model of substituted ureas.

Eur J Med Chem. 2009 Mar;44(3):1240-9. doi: 10.1016/j.ejmech.2008.09.016. Epub 2008 Sep 23.

PubMed ID

18947905 [ View in PubMed

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Abstract

A three-dimensional (3D) quantitative pharmacophore model was developed from a training set of structurally diverse substituted ureas against Raf-1 kinase, which was well validated to be highly predictive by two methods, namely, test set prediction and Cat-Scramble method. Then a virtual database searching was performed with the pharmacophore model as a 3D query, and the bioactivities of the retrieved hits were predicted by the pharmacophore. Subsequently, molecular docking was carried out on the selected hits whose estimated IC(50) was less than 1 microM. Finally, 29 hits were identified as potential leads against Raf-1 kinase, which exhibited good estimated activities, high docking scores, similar binding mode to experimentally proven compounds and favorable drug-like properties. The study may facilitate the discovery and rational design of novel leads with potent inhibitory activity targeting Raf-1 kinase.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Sorafenib	RAF proto-oncogene serine/threonine-protein kinase	IC 50 (nM)	12	N/A	N/A	Details