title: Exploration of the valproic acid binding site on histone deacetylase 8 using docking and molecular dynamic simulations.
abstract: Epigenetic therapy is an important focus of research for drug development in the treatment of cancer. Valproic acid (VPA) is an HDAC inhibitor that has been evaluated in clinical studies. Despite its success in treating cancer, the mechanism of inhibition of VPA in HDAC is unknown. To this end, we have used docking and molecular dynamic simulations to investigate VPA binding to HDAC, employing both native and rebuilt 3-D structures. The results showed that VPA, via its carboxyl group, coordinates the Zn atom and other local residues (H141-142 and Y360) located at the catalytic site (CS) of HDAC. This causes electrostatic and hydrogen bonding interactions while having little interaction with the hydrophobic side chains, resulting in a low affinity. However, after several docking studies on different native HDAC 3-D structures and after using several snapshots from MD simulations, it became apparent that VPA bound with highest affinity at a site located at the acetyl-releasing channel, termed the hydrophobic active site channel (HASC). The affinity of VPA for HASC was due to its highly hydrophobic properties that allow VPA to take part in van der Waals interactions with Y18, I19, Y20, V25, R37, A38, V41, H42, I135 and W137, while VPA's carboxylate group has several hydrogen bonding interactions with the backbones of S138, I19, N136 and W137. MD simulations showed that the HASC door continuously opened and closed, which affected the affinity of VPA to the HASC, but the affinity toward the HASC was consistently higher than that obtained for the CS, suggesting that the HASC could be involved in the mechanism of inhibition.
authors.affiliation: Sección de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, Mexico City, Mexico.
authors.forename: Jorge Antonio
authors.initials: JA
authors.lastname: Bermúdez-Lugo
authors.forename: Oscar
authors.initials: O
authors.lastname: Perez-Gonzalez
authors.forename: Martha Cecilia
authors.initials: MC
authors.lastname: Rosales-Hernández
authors.forename: Ian
authors.initials: I
authors.lastname: Ilizaliturri-Flores
authors.forename: José
authors.initials: J
authors.lastname: Trujillo-Ferrara
authors.forename: Jose
authors.initials: J
authors.lastname: Correa-Basurto
mesh_terms: D000465:Algorithms; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006655:Histone Deacetylases / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D013499:Surface Properties; D014635:Valproic Acid / Q000737:chemistry*
chemical_list: D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D014635:Valproic Acid; C409470:HDAC8 protein, human; D006655:Histone Deacetylases