PLS DA for the best model afforded excellent separation of the seven groups of kinases. the cross validated squared except correlation Inhibitors,Modulators,Libraries coefficients fell between 0. 93 0. 98 for six of the groups, while for the more diverse tyrosine kinase like kinase group it was 0. 89. As explained in the Methods section, PLS DA models create regression equations for each of the modelled classes and thus identify properties that are more typical, or even unique, for a particular class compared to the other classes. Thus, inspection of the alignment based PLS DA regression equation exploiting z scale descrip tors reveals that in some cases the description of the physico chemical properties of very short sequence stretches and even of single residues are sufficient to sep arate all members of one kinase group from all other kinases.

In one Inhibitors,Modulators,Libraries such example, when we inspected the alignment based PLS DA model we revealed Inhibitors,Modulators,Libraries that a con served proline residue located surrounded by two hydro phobic amino acids in the activation loop of the TKs sequences is the sufficient pattern for class separation. In the majority of the cases this triplet is embraced by two positively charged lysine or arginine residues. Analysis of the alignment independent PLS DA model exploiting AAC DC descriptors further identifies that groups of kinases are often distinguished by the model by small sets of dipeptides. Such identified specific sequence residues or patterns, which may be identified by our models, could accordingly potentially be addressed in the design of targeted and Inhibitors,Modulators,Libraries multi targeted drugs.

In fact, a few such amino acids have been previ ously exploited in drug design for kinases. This includes Inhibitors,Modulators,Libraries the so called gatekeeper residue, which is a bulky amino acid present in most kinases, while 20% of the kinases have a threonine at this position. The property was used in design of selectivity for ABL kinase inhibitors. A study of Cohen this et al. designed inhibitors for RSK family kinases by targeting two selectivity filters in the ATP binding site, namely the threonine gatekeeper and a cysteine residue, which is an uncommon amino acid in the kinases active site. These two amino acids that distinguishes RSKs from other pro tein kinases were sufficient to confer high activity of the designed inhibitor. Although we here limited PLS DA modelling to separa tion of seven major groups of the kinase superfamily the analysis can be performed hierarchically at any resolu tion, e. g, to delineate particular families, subfamilies, and even single kinases. In the subsequent studies we created quantitative mod els for kinase inhibitor interaction activities using the six types of kinase descriptions and performing correlations using SVM, PLS, k NN, and decision trees.