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

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.

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; MM – molecular mechanics; MMGBSA – Molecular-Mechanics-Generalized-Born-Surface-Area; 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.