Zinc binding in HDAC inhibitors: a DFT study.
Histone 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.
Wang
Difei
D
Department of Chemistry and Biochemistry and Walther Cancer Research Center, University of Notre Dame, Notre Dame, Indiana 46556-5670, USA.
Helquist
Paul
P
Wiest
Olaf
O
D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D014867:Water / Q000737:chemistry; D015032:Zinc / Q000737:chemistry*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D008024:Ligands; D014867:Water; D006655:Histone Deacetylases; D015032:Zinc