postulation that the inhibitor is interacting with the nicotinamide-binding pocket of
Sirt2. AGK2 inhibits Sirt2 with an IC 50 value of 3.5 μM and shows more than
tenfold selectivity over Sirt1 and Sirt3. AGK2 is a valuable chemical tool since it
also displayed the ability to block α-synuclein-mediated toxicity in a Parkinson’s
disease model, possibly by modulating tubulin acetylation regulated by Sirt2 [94].
Another approach to discover novel sirtuin inhibitors was based on fragments
identified by random screening and applying structure-based design to optimize the
Fig. 4 (a) X-ray structure of human Sirt3 (white ribbon) in complex with Carba-NAD
+ (yellow
sticks) and acetylated peptide (green) (PDB ID: 4FVT). (b) X-ray structure of human Sirt2 in
complex with the selective inhibitor SirReal2 (16; green sticks) (PDB ID: 4RMH). Only the
residues in the binding pocket are shown. Hydrogen bonds are displayed as yellow dashed lines
and the water molecule as a red sphere
N
N
H
O
O
Cl
Cl
N
O
N
H
O
N
O
NH 2
O
N
H
N
S
S
N
N
13
14
15
O
NH
NH 2
O
16
O
N
H
N
S
S
N
N
Br
17
Fig. 5 Molecular structures of sirtuin inhibitors mentioned in the text
464
D. Robaa et al.