Abstract
Histone deacetylases (HDACs) are a family of proteins whose main function is the removal of acetyl groups from lysine residues located on histone and non-histone substrates, which regulates gene transcription and other activities in cells. HDAC1 dysfunction has been implicated in cancer development and progression; thus, its inhibition has emerged as a new therapeutic strategy. Two additional metal binding sites (Site 1 and Site 2) in HDACs have been described that are primarily occupied by potassium ions, suggesting a possible structural role that affects HDAC activity. In this work, we explored the structural role of potassium ions in Site 1 and Site 2 and how they affect the interactions of compounds with high affinities for HDAC1 (AC1OCG0B, Chlamydocin, Dacinostat and Quisinostat) and SAHA (a pan-inhibitor) using molecular docking and molecular dynamics (MD) simulations in concert with a Molecular-Mechanics-Generalized-Born-Surface-Area (MMGBSA) approach. Four models were generated: one with a potassium ion (K + ) in both sites (HDAC1 k ), a second with K + only at site 1 (HDAC1 ks1 ), a third with K + only at site 2 (HDAC1 ks2 ) and a fourth with no K + (HDAC1 wk ). We found that the presence or absence of K + not only impacted the structural flexibility of HDAC1, but also its molecular recognition, consistent with experimental findings. These results could therefore be useful for further structure-based drug design studies addressing new HDAC1 inhibitors.
Original language | English |
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Pages (from-to) | 584-610 |
Number of pages | 27 |
Journal | Journal of Biomolecular Structure and Dynamics |
Volume | 37 |
Issue number | 3 |
DOIs | |
State | Published - 11 Feb 2019 |
Keywords
- 3D–three-dimensional
- GAFF–Generalized Amber Force Field
- HATs–Histone acetyltransferases
- HDAC1
- HDACi–Histone deacetylase inhibitor
- HDACs–Histone deacetylases
- HIF–hypoxia-inducible factor
- Hsp-90–heat-shock protein
- MD–Molecular dynamic
- MMGBSA–Molecular-Mechanics-Generalized-Born-Surface-Area
- MM–molecular mechanics
- NAD–Nicotinamide adenine dinucleotide
- PDB–protein data bank
- RMSD–root mean square deviation
- RMSF–root mean square fluctuation
- Rg–radius of gyration
- SAHA–suberanilohydroxamic acid
- ZBG–zinc-binding group
- docking
- molecular dynamics
- molecular mechanics-generalized-Born surface area