Toward Selective Histone Deacetylase Inhibitor Design: Homology Modeling, Docking Studies, and Molecular Dynamics Simulations of Human Class I Histone Deacetylases

Histone deacetylases (HDACs) play an important role in gene transcription. Inhibitors of HDACs
induce cell differentiation and suppress cell proliferation in tumor cells. Although many HDAC
inhibitors have been designed and synthesized, selective inhibition for class I HDAC isoforms
is a goal that has yet to be achieved. To understand the difference between class I HDAC
isoforms that could be exploited for the design of isoform-specific HDAC inhibitors, we have
built three-dimensional models of four class I histone deacetylases, HDAC1, HDAC2, HDAC3,
and HDAC8. Comparison of the homology model of HDAC8 with the recently published X-ray
structure shows excellent agreement and validates the approach. A series of HDAC inhibitors
were docked to the homology models to understand the similarities and differences between
the binding modes. Molecular dynamic simulations of these HDAC−inhibitor complexes indicate
that the interaction between the protein surface and inhibitor is playing an important role;
also some active site residues show some flexibility, which is usually not included in routine
docking protocols. The implications of these results for the design of isoform-selective HDAC
inhibitors are discussed.