Inhibition and Mechanism of HDAC8 Revisited

Histone deacetylases (HDACs) have
found intense interest as drug
targets for a variety of diseases, but there is disagreement about
basic aspects of the inhibition and mechanism of HDACs. QM/MM calculations
of HDAC8 including a large QM region provide a model that is consistent
with the available crystal structures and structure–activity
relationships of different HDAC inhibitors. The calculations support
a spontaneous proton transfer from a hydroxamic acid to an active
site histidine upon binding to the zinc. The role of the H142/D176
catalytic dyad as the general base of the reaction is elucidated.
The reasons for the disagreements between previous proposals are discussed.
The results provide detailed insights into the unique mechanism of
HDACs, including the role of the two catalytic dyads and function
of the potassium near the active site. They also have important implications
for the design of novel inhibitors for a number of HDACs such as the
class IIa HDACs.