Virtual Screening for Kinase Targets

Ingo      Muegge; Istvan   J.   Enyedy

Abstract

Kinases have become a major area of drug discovery and structure-based design. Hundreds of 3D structures for more than thirty different kinases are available to the public. High structural and sequence homology within the kinase gene family makes the remaining kinases ideal targets for homology modeling and virtual screening. Somewhat surprisingly, however, the number of publications about virtual screening of kinases is very low. Therefore, rather than reviewing the field of virtual screening for kinases, we attempt here a hybrid approach of presenting what is known and common practice together with new studies on CDK2 and SRC kinase. To illustrate the challenges and pitfalls of virtual screening for kinase targets we focus on the question of how ranking is influenced by the database screened, the docking scheme, the scoring function, the activity of the compounds used for testing, and small changes in the binding pocket. In addition, a case study of finding irreversible inhibitors of ErbB2 through in silico screening is presented.

Keywords: database searching, rational drug design, lead identification, atp binding pocket

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