Kinases binding mode/selectivity

Furet P, Caravattti G, Priestle J, Sowadski J, Trinks U, Traxler P. Modeling study of protein kinase inhibitors Binding mode of staurosporine-origin of the selectivity of CGP 52 411. J Comp Aid Mol Design 1995 9 465-472. 

The 6-acrylamido-4-anilinoquinazolines constitute another class of irreversible inhibitor targeted at the EG Fr tyrosine kinase. This type of inhibitor has been derived from the very potent (6 pM) and selective 4-anilinoquinazolines, e.g., PD-0153035 [4e], A detailed description of the binding mode of the 4-anilinoquinazolines is given in Section 7.4.1. The Michael acceptor at the 6-position of the 4-anilino-... 

Myrianthopoulos V, KritsanidaM, Gaboriaud-Kolar N, Magiatis P, Ferandin Y, Durieu E et al (2013) Novel inverse binding mode of indirubin derivatives yields improved selectivity for DYRK kinases. ACS Med Chem Lett 4 22-26... 

Figure 4.3 Binding modes for medicines that extend from the purine site into the selectivity pocket of protein kinases. Key hydrogen bonds are shown as dotted lines and hydrophobic interactions in the selectivity pocket are shown as arcs.

It is difficult to deconvolute how kinase inhibitor binding mode has implications in the clinic. In general, selectivity tends to increase in the order (i) purine site, (ii) selectivity pocket, and (iii) allosteric site. The ability to overcome resistance mutations in cancer therapy tends to be inversely related to this selectivity pattern. Accordingly, allosteric kinase inhibition may become a preferred mechanism for clinical indications other than cancer. 

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