Figure 2.

(a) Representation of cryo-EM structure of 14 (carbon = magenta; nitrogen = blue; fluorine = light blue; key hydrogens = white; yellow dashes = H-bonds) bound to p97 at an allosteric site in the D2 domain.¹⁶ The phenyl indole binds in a deep pocket, but the side-chain points directly into solvent and engages in no contacts with protein residues. (b) Molecular modeling-derived binding mode that accounts for side-chain SAR. Key inhibitor (14) side-chain–protein interactions include H-bonds (yellow dashes) with Gln494, Glu498, Glu534, and Cys535, as well as solvent shielding of the terminal iPr group by the side-chain indole of Trp476.