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.
Wang
Di-Fei
DF
Walther Cancer Research Center and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556-5670, USA.
Helquist
Paul
P
Wiech
Norbert L
NL
Wiest
Olaf
O
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D000099186:Histone Deacetylase 3
D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D007527:Isoenzymes; D008024:Ligands; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C110550:HDAC1 protein, human; C409470:HDAC8 protein, human