Inhibitors Binding modes

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. 

Chung C, Dean AW, Woolven JM, Bamborough P (2012) Fragment-based discovery of bromodomain inhibitors part 1 inhibitor binding modes and implications for lead discovery. J Med Chem 55 576-586... 

Type I and type II kinase inhibitor binding modes are exemplified in Figure 3.3, which shows PD166326 (6, a) and imatinib (7, b) bound to ABL, represented by ribbon structures (PDB lOPK,11 and IIEP,12 respectively). In the latter, the DFG-out conformation of the activation loop reveals the allosteric site occupied by the benzylpiperazine moiety of imatinib, 7. 

Figure 3.3 Comparison of Type I (a) and Type II (b) kinase inhibitor binding modes.

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. 

---