Insights into structural features of HDAC1 and its selectivity inhibition elucidated by Molecular dynamic simulation and Molecular Docking

Yudibeth Sixto-López, Martiniano Bello, José Correa-Basurto

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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 languageEnglish
Pages (from-to)584-610
Number of pages27
JournalJournal of Biomolecular Structure and Dynamics
Volume37
Issue number3
DOIs
StatePublished - 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

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