Figure 2.

Hit design via fragment expansion. Diversification of the inactive fragment compound 1 by amination yields the active hit compound 3. The crystal structure of the p38αMAPK:1 (PDB code 4ZTH) identifies key molecular recognition features that are retained in the p38αMAPK:3 (PDB code 4EWQ). The key features include the position and net charge of the pyridine ring nitrogen that allows H-bonding with the peptide backbone of the kinase hinge region and the occupancy of the localized hydrophobic pocket by the vicinal phenyl substituent. The representation and orientation of structures shown are as in Figure 1B.