Figure 10.

Computationally probing the druggability of the S6–S7 pocket. (A) Dehydrons (green dashes) mapped onto the final frame from the simulation of V143A destabilizing mutant of the p53 DBD. Two new dehydrons (208Asp–213Arg) in the S6–S7 turn of the domain are identified and highlighted in circle. (B) Fragment mapping carried out on a mutant p53 DBD conformation taken from the MD simulations (where the pocket is open) using FTMap identified the S6–S7 pocket as the primary pocket with the largest cluster of a range of fragments. (C) Benzene mapping simulations of the mutant p53 DBD identified a cluster of benzenes at the S6–S7 pocket. The S6–S7 turn is colored in green. (D–F) Structure based search of the S6–S7 pocket in p53 DBD identified small molecules that are bound to a similar pocket in beta-lactoglobulin-dodecane trimethylamine, Dodecyl sulfate and [N,N-di(pyridin-2-yl-kappaN)dodecanamide]rhodium respectively. (G) Pocket as observed in the WT NMR structure (PDB ID: 2FEJ).