Figure 5.

IRAK4 cocrystal structures of the methylbenzimidazole-based 38 (A, PDB 8ATN) (Table 8) and superposition with the cocrystal structure of the indazole-based compound 40 (B, PDB 8BR6) (Table 9). The chemical variation in the core induced no positional shift. Moreover, the methylsulfonylethyl and the 2-hydroxy-propan-2-yl substituent take equivalent positions when used as a front pocket substituent. A remarkable difference between the two X-ray protein conformations is the reorientation of the Asp329 side chain, enabling a hydrogen bond to be formed with the hydroxyl group of the pyridyl substituent of 40. Moreover, the aromatic plane of the Tyr264 side chain is rotated in response to the binding of the methylated core.