ORIGINAL PAPER Exploration of the valproic acid binding site on histone deacetylase 8 using docking and molecular dynamic simulations Jorge Antonio Bermúdez-Lugo & Oscar Perez-Gonzalez & Martha Cecilia Rosales-Hernández & Ian Ilizaliturri-Flores & José Trujillo-Ferrara & Jose Correa-Basurto Received: 7 March 2011 /Accepted: 9 September 2011 /Published online: 4 October 2011 # Springer-Verlag 2011 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, coordi- nates 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. Keywords Anticancer drugs . Catalytic site . Hydrophobic active site channel . Theoretical studies Introduction The epigenetic processes controlled by histone acetyltrans- ferase (HAT) and histone deacetylase (HDAC) have been widely studied, as these proteins represent emerging targets for functional modification in certain diseases, such as cancer [1] and HIV [2]. HDAC belongs to a family of 18 proteins that catalyzes the deacetylation of acetylated ε-amino lysines in histone tails. The proteins are divided into four groups based on their homology domain, their cofactors, and their ability to shuttle between the nucleus and the cytoplasm. HDAC isoforms 1, 2, 3 and 8 belong to class I, while isoforms 4, 5, 6, 7, 9 and 10 belong to class II. The class I isoforms are usually located in the nucleus and require a zinc ion (Zn) for activity, while the class II isoforms can be located in either the nucleus or the cytoplasm, depending on the cell's metabolic needs. Class IV contains only one isoform, HDAC11, which significantly differs in its domain composition compared to other HDAC isoforms. It is believed that HDAC11 diverged earlier in evolution than the other isoforms. Finally, class III consists J. A. Bermúdez-Lugo : M. C. Rosales-Hernández : I. Ilizaliturri-Flores : J. Trujillo-Ferrara : J. Correa-Basurto (*) Laboratorio de Modelado Molecular y Bioinformatica, Sección de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón, 11340, Mexico City, Mexico e-mail: jcorreab@ipn.mx O. Perez-Gonzalez Experimental Oncology Laboratory, National Institute of Pediatrics, Mexico City, Mexico J Mol Model (2012) 18:2301–2310 DOI 10.1007/s00894-011-1240-z