TY - JOUR
T1 - Exploration of the valproic acid binding site on histone deacetylase 8 using docking and molecular dynamic simulations
AU - Bermúdez-Lugo, Jorge Antonio
AU - Perez-Gonzalez, Oscar
AU - Rosales-Hernández, Martha Cecilia
AU - Ilizaliturri-Flores, Ian
AU - Trujillo-Ferrara, José
AU - Correa-Basurto, Jose
N1 - Funding Information:
This study was conducted thanks to grants from Consejo Nacional de Ciencia y Tecnología, (132353), Instituto de Ciencia y Tecnología del Distrito Federal-Mexico, (PIRIVE09-9), Miguel Aleman A.C Foundation, and Secretaria de Investigación y Posgrado: Estimulo de desempeño en Investigación, Projects: 20110786 and Megaproyecto, Sistema de Becas por Exclusividad de Comisión de Cooperación y Fomento de Actividades Académicas del Instituto Politécnico Nacional. We also gratefully acknowledge the scholarships from Programa Institucional de Formación de Investigadores and from Consejo Nacional de Ciencia y Tecnología to JABL.
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
KW - Anticancer drugs
KW - Catalytic site
KW - Hydrophobic active site channel
KW - Theoretical studies
UR - http://www.scopus.com/inward/record.url?scp=84864718249&partnerID=8YFLogxK
U2 - 10.1007/s00894-011-1240-z
DO - 10.1007/s00894-011-1240-z
M3 - Artículo
C2 - 21968575
SN - 1610-2940
VL - 18
SP - 2301
EP - 2310
JO - Journal of Molecular Modeling
JF - Journal of Molecular Modeling
IS - 6
ER -