title: Exploring the potential binding sites of some known HDAC inhibitors on some HDAC8 conformers by docking studies.
abstract: We describe the conformational behavior of histone deacetylase 8 (HDAC8) using molecular dynamics (MD) simulations. HDAC8 conformers were used for the docking studies using some known HDAC inhibitors (HDACi) suberoylanilide hydroxamic acid (SAHA), valproic acid (VPA), aroyl-pyrrole-hydroxy-amide (APHA-8) and tubacin to explore their interactions, binding modes, free energy values. The MD simulation show that HDAC8 make important surface changes at the catalytic site (CS) entrance as well as at two entrances locations in the 14-Å tunnel. In addition, we identify an alternate entrance to the 14-Å tunnel named adjacent to the catalytic site pocket (ACSP). By using docking studies, it was possible to elucidate the importance of hydrophobic and π-π interactions that are the most important for the ligand-HDAC8 complex structural stabilization. In conclusion, the ligand flexibility, molecular weight and chemical moieties (hydroxamic acid, aryl and aliphatic moieties) are the principal properties required to increase the binding affinity on HDAC8.
authors.affiliation: Laboratorio de Modelado Molecular y Diseño de Fármacos (Laboratory of Molecular Modeling and Drug Design), Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, 11340, Mexico.
authors.forename: Yudibeth
authors.initials: Y
authors.lastname: Sixto-López
authors.forename: José A
authors.initials: JA
authors.lastname: Gómez-Vidal
authors.forename: José
authors.initials: J
authors.lastname: Correa-Basurto
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011487:Protein Conformation / Q000187:drug effects; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases