jo070739s_si_001.pdf (38.39 kB)
Zinc Binding in HDAC Inhibitors: A DFT Study
journal contribution
posted on 2007-07-06, 00:00 authored by Difei Wang, Paul Helquist, Olaf WiestHistone deacetylases (HDACs) are attractive targets for the
treatment of cancers and a variety of other diseases. Most
currently studied HDAC inhibitors contain hydroxamic acids,
which are potentially problematic in the development of
practical drugs. DFT calculations of the binding modes and
free energies of binding for a variety of other functionalities
in a model active site of HDAC are described. The
protonation state of hydroxamic acids in the active site and
the origin of the high affinity are discussed. These results
emphasize the importance of a carefully chosen pKa for zinc
binding and provide guidance for the design of novel, non-hydroxamic acid HDAC inhibitors.