Figure 3.

Binding pose for compound 15 c in the E (left) and Z (right) configurations from pharmacophore‐guided docking. Because compound 15 c is not selective for Sirt2, and modification of the primary amide group leads to complete loss of activity, binding of the nicotinamide moiety to residues I169 and D170 like NAD⁺is expected (C‐site). For (E)‐15 c, the tert‐butyl group points towards the hydrophobic acetyl‐lysine channel while exposing the polar carbamate towards the solvated entrance region. After photoisomerization, the phenyl group shifts to the more hydrophobic binding site, leading to unfavourable interactions for the carbamate; this might explain the decrease in activity. However, the binding of the nicotinamide moiety is not expected to be affected. The conformation of (Z)‐15 c was validated by analyses of potential energies in relation the CCNN‐dihedral angles (Figure S7). The pharmacophore region for an amide group is shown as green sphere.