Computational Exploration of Zinc Binding Groups for HDAC Inhibition

Histone
deacetylases (HDACs) have emerged as important drug targets
in epigenetics. The most common HDAC inhibitors use hydroxamic acids
as zinc binding groups despite unfavorable pharmacokinetic properties.
A two-stage protocol of M05-2X calculations of a library of 48 fragments
in a small model active site, followed by QM/MM hybrid calculations
of the full enzyme with selected binders, is used to prospectively
select potential bidentate zinc binders. The energetics and interaction
patterns of several zinc binders not previously used for the inhibition
of HDACs are discussed.