Kinase-inhibitor-likeness

Non-selective PKB inhibitors have been extensively used as tool compounds to elucidate the role of this kinase in the biology of human cancers. Thus, PKB isoforms are potently inhibited by promiscuous kinase inhibitors like staurosporine (compound 22, Fig. 5 IC50 = 48 to 11 nM for PKBa) [131-133] and derivatives thereof (e.g., compound 23, Fig. 5) [134]. Another example of a potent and non-selective pan-PKB inhibitor is Ro-31-8220 (compound 24, Fig. 5), a PKC inhibitor (IC50 = 10 nM) [135] that also interferes with PKB kinase activity (IC50 = 240 nM for PKBa). 

Now the whole trick of this procedure is the following. Prior to PCA, artificial compounds (or a real set of reference compounds) are added to the data matrix X. These additional data points (library spikes ) have coordinates that represent idealized properties of the library. For example, if the aim is to generate a library for the cannabinoid receptor family, possible coordinates of the idealized artificial compound might be 1 for drug-likeness, 1 for GPCR-ligand-likeness, 1 for cannabinoid-likeness, 0 for dopamine-likeness, 0 for kinase-inhibitor-likeness, and so forth. In this example, the value T indicates the maximum value of a property (presence of a feature), 0 indicates minimum values (absence of a feature). Of course, appropriate prediction models must be at hand. 

Briem, H. and Guenther, J. (2005) Classifying kinase inhibitor-likeness by using machine-learning methods. ChemBioChem, 6 (3), 558—566. 

Structure-Activity Relationships of Polo-Like Kinase Inhibitors. 271... 

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