Kinase-ligand-likeness

Table 13.2 Rank order of virtual combinatorial libraries based on predicted drug-likeness, cytotoxicity, GPCR-ligand likeness, and kinase-ligand likeness. ++ indicates pronounced positive prediction, + mediocre to slightly positive prediction, - negative prediction (absence of the property). 

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. 

Besides direct apoptosis effectors, there are a number of other diugs which influence the above explained apoptosis pathways more indirectly. This class of diugs includes molecules which inhibit survival pathways like e.g. the Ras/Raf kinase pathway, the NF-kB pathway and many others. Also inhibitors of survival cytokines which are sometimes produced by cancer cells in an autocrine fashion can render cells susceptible to apoptosis and, hence, effective cancer therapy. These include, but are not limited to, ligands for dependence receptors and cytokines like e.g. interleukin-4. 

Bouaboula M, Perrachon S, Milligan L, Canat X, Rinaldi-Carmona M, Portier M, Barth F, Calandra B, Pecceu F, Lupker J, Maffrand JP, Le Fur G, Casellas P. A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor 1. Evidence for a new model of receptor/ligand interactions. J Biol Chem 1997 272 22330-22339. 

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