Kinase Inhibitors Designed to Crate Floppy Regions

3 Kinase Inhibitors Designed to Crate Floppy Regions 

The crating drug concept is evaluated by revisiting a recent redesign of imatinib [15], the anticancer drug adopted to treat chronic myeloid leukemia (CML) [3, 4], As previously described in Chaps. 7 and 8, this inhibitor was originally designed to 

The JNK inhibitory activity of WBZ 4 (K ) 51 nM) has being experimentally confirmed and is not found in imatinib [14], In fact, as our dynamic analysis shows, this affinity results from a structure-inducing role of WBZ 4 that, in contrast with imatinib, acts as a protector and hence a stabilizer of a specific JNK conformation. As shown below, this conformation introduces an additional hydrogen bond in the nucleotide-binding loop. This revision of the inhibitory impact of WBZ 4 on the floppier JNK supports our proposed strategy to control the target-induced folding in a selective manner. 

As MD computations corroborate [21], the M111-N114 hydrogen bond (N-0 distance 3.4 A) is unsustainable in the uncomplexed JNK or even in the JNK/imatinib complex. The latter forms the bond intermittently and ephemerally but its average lifetime, r = 12 ps over 20 runs spanning 730 ns, indicates metastability (Fig. 11.4a). This metastability results primarily from the lack of enough 

Kinase Kit Jnkl Jnk3 MAPK6 MAPK1 p38a p38y 

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