ArticleJournal of molecular modeling2012
Exploration of the valproic acid binding site on histone deacetylase 8 using docking and molecular dynamic simulations.
Article in Journal of molecular modeling, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 34 citations in OpenAlex.
- The Importance of Structural Water in HDAC8 for Correct Binding Pose Applied for Drug Design of Anticancer Molecules.Anti-cancer agents in medicinal chemistry · 2024Article
- A Review on Molecular Docking on HDAC Isoforms: Novel Tool for Designing Selective Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2023Review
- TP-DDI: A Two-Pathway Deep Neural Network for Drug-Drug Interaction Prediction.Interdisciplinary sciences, computational life sciences · 2022Article
- Exploring the inhibitory activity of valproic acid against the HDAC family using an MMGBSA approach.Journal of computer-aided molecular design · 2020Article
- Hydroxamic acid derivatives as HDAC1, HDAC6 and HDAC8 inhibitors with antiproliferative activity in cancer cell lines.Scientific reports · 2020Article
- Valproic acid inhibits glioblastoma multiforme cell growth via paraoxonase 2 expression.Oncotarget · 2017Article
- Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents.Molecules (Basel, Switzerland) · 2015Review
- The histone deacetylase inhibitor valproic acid sensitizes diffuse large B-cell lymphoma cell lines to CHOP-induced cell death.American journal of translational research · 2013Article
- Prostatic cell-specific regulation of the synthesis of MUC1-associated sialyl Lewis a.PloS one · 2013Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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