Skip to content
2000
Volume 21, Issue 7
  • ISSN: 1573-4064
  • E-ISSN: 1875-6638

Abstract

Background

Overexpression of HDAC8 was observed in various cancers and inhibition of HDAC8 has emerged as a promising therapeutic approach in recent decades.

Objective

This review aims to facilitate the discovery of novel selective HDAC8 inhibitors by analyzing the structural scaffolds of 66 known selective HDAC8 inhibitors, along with their IC values against HDAC8 and other HDACs.

Methods

The inhibitors were clustered based on structural symmetry, and common pharmacophores for each cluster were identified using Phase. Molecular docking with all HDACs was performed to determine binding affinity and crucial interacting residues for HDAC8 inhibition. Representative inhibitors from each cluster were subjected to molecular dynamics simulation to analyze RMSD, RMSF, active site amino acid residues, and crucial interacting residues responsible for HDAC8 inhibition. The study reviewed the active site amino acid information, active site cavities of all HDACs, and the basic structure of Zn2+ binding groups.

Results

Common pharmacophores identified included AADHR_1, AADDR_1, ADDR_1, ADHHR_1, and AADRR_1. Molecular docking analysis revealed crucial interacting residues: HIS-142, GLY-151, HIS-143, PHE-152, PHE-208 in the main pocket, and ARG-37, TYR-100, TYR-111, TYR-306 in the secondary pocket. The RMSD of protein and RMSF of active site amino acid residues for stable protein-ligand complexes were less than 2.4 Å and 1.0 Å, respectively, as identified from MD trajectories. The range of Molecular Mechanics Generalized Born Surface Area (MM-GBSA) ΔG predicted from MD trajectories was between -15.8379 Å and -61.5017 Å kcal/mol.

Conclusion

These findings may expedite the rapid discovery of selective HDAC8 inhibitors subject to experimental evaluation.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/mc/10.2174/0115734064320232240709105228
2024-07-19
2026-02-01

  • From This Site

    /content/journals/mc/10.2174/0115734064320232240709105228
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. RaghuramN. CarreroG. StasevichT.J. McNallyJ.G. Th’ngJ. HendzelM.J. Core histone hyperacetylation impacts cooperative behavior and high-affinity binding of histone H1 to chromatin.Biochemistry201049214420443110.1021/bi100296z 20411992
     [Google Scholar]
  2. SinghR.K. MandalT. BalasubramanianN. CookG. SrivastavaD.K. Coumarin-suberoylanilide hydroxamic acid as a fluorescent probe for determining binding affinities and off-rates of histone deacetylase inhibitors.Anal. Biochem.2011408230931510.1016/j.ab.2010.08.040 20816742
     [Google Scholar]
  3. ThangapandianS. JohnS. LeeY. KimS. LeeK.W. Dynamic structure-based pharmacophore model development: a new and effective addition in the histone deacetylase 8 (HDAC8) inhibitor discovery.Int. J. Mol. Sci.201112129440946210.3390/ijms12129440 22272142
     [Google Scholar]
  4. AndreiniC. BanciL. BertiniI. RosatoA. Counting the zinc-proteins encoded in the human genome.J. Proteome Res.20065119620110.1021/pr050361j 16396512
     [Google Scholar]
  5. KrennHrubecK. MarshallB.L. HedglinM. VerdinE. UlrichS.M. Design and evaluation of ‘Linkerless’ hydroxamic acids as selective HDAC8 inhibitors.Bioorg. Med. Chem. Lett.200717102874287810.1016/j.bmcl.2007.02.064 17346959
     [Google Scholar]
  6. OehmeI. DeubzerH.E. WegenerD. PickertD. LinkeJ.P. HeroB. Kopp-SchneiderA. WestermannF. UlrichS.M. von DeimlingA. FischerM. WittO. Histone deacetylase 8 in neuroblastoma tumorigenesis.Clin. Cancer Res.2009151919910.1158/1078‑0432.CCR‑08‑0684 19118036
     [Google Scholar]
  7. VanniniA. VolpariC. FilocamoG. CasavolaE.C. BrunettiM. RenzoniD. Crystal structure of a eukaryotic zinc−dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor.Proc. Natl. Acad. Sci.2004150641506910.1073/pnas.0404603101
     [Google Scholar]
  8. WuJ. DuC. LvZ. DingC. ChengJ. XieH. ZhouL. ZhengS. The up-regulation of histone deacetylase 8 promotes proliferation and inhibits apoptosis in hepatocellular carcinoma.Dig. Dis. Sci.201358123545355310.1007/s10620‑013‑2867‑7 24077923
     [Google Scholar]
  9. AttenniB. OntoriaJ.M. CruzJ.C. RowleyM. Schultz-FademrechtC. SteinkühlerC. JonesP. Histone deacetylase inhibitors with a primary amide zinc binding group display antitumor activity in xenograft model.Bioorg. Med. Chem. Lett.200919113081308410.1016/j.bmcl.2009.04.011 19410459
     [Google Scholar]
  10. SubramanianS. BatesS.E. WrightJ.J. Espinoza-DelgadoI. PiekarzR.L. Clinical toxicities of histone deacetylase inhibitors.Pharmaceuticals2010392751276710.3390/ph3092751 27713375
     [Google Scholar]
  11. AdhikariN. AminS.A. JhaT. Selective and nonselective HDAC8 inhibitors: A therapeutic patent review.Pharm. Pat. Anal.20187625927610.4155/ppa‑2018‑0019 30632447
     [Google Scholar]
  12. HoT.C.S. ChanA.H.Y. GanesanA. Thirty years of HDAC inhibitors: 2020 insight and hindsight.J. Med. Chem.20206321124601248410.1021/acs.jmedchem.0c00830 32608981
     [Google Scholar]
  13. BassA.K.A. El-ZoghbiM.S. NageebE.S.M. MohamedM.F.A. BadrM. Abuo-RahmaG.E.D.A. Comprehensive review for anticancer hybridized multitargeting HDAC inhibitors.Eur. J. Med. Chem.202120911290410.1016/j.ejmech.2020.112904 33077264
     [Google Scholar]
  14. HeshamH.M. LasheenD.S. AbouzidK.A.M. Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer.Med. Res. Rev.20183862058210910.1002/med.21505 29733427
     [Google Scholar]
  15. ManalM. ChandrasekarM.J.N. Gomathi PriyaJ. NanjanM.J. Inhibitors of histone deacetylase as antitumor agents: A critical review.Bioorg. Chem.201667184210.1016/j.bioorg.2016.05.005 27239721
     [Google Scholar]
  16. ZhaoC. DongH. XuQ. ZhangY. Histone deacetylase (HDAC) inhibitors in cancer: A patent review (2017-present).Expert Opin. Ther. Pat.201730426327410.1080/13543776.2020.1725470
     [Google Scholar]
  17. DebnathS. DebnathT. MajumdarS. ArunasreeM.K. AparnaV. A combined pharmacophore modeling, 3D QSAR, virtual screening, molecular docking, and ADME studies to identify potential HDAC8 inhibitors.Med. Chem. Res.201625112434245010.1007/s00044‑016‑1652‑5
     [Google Scholar]
  18. DebnathS. NathP. NathR.K. Identification of novel HDAC8 inhibitors using pharmacophore based virtual screening, 3D QSAR and molecular docking approach. Am. J. PharmTech.Res.2014425326710.21276/ajptr
     [Google Scholar]
  19. BozorgiA.H.A. ZarghiA. Search for the pharmacophore of histone deacetylase inhibitors using pharmacophore query and docking study.Iran. J. Pharm. Res.201413411651172
     [Google Scholar]
  20. KashyapK. KakkarR. Pharmacophore-enabled virtual screening, molecular docking and molecular dynamics studies for identification of potent and selective histone deacetylase 8 inhibitors.Comput. Biol. Med.202012310385010.1016/j.compbiomed.2020.103850 32658783
     [Google Scholar]
  21. KashyapK. KakkarR. An insight into selective and potent inhibition of histone deacetylase 8 through induced−fit docking, pharmacophore modeling and QSAR studies.J. Biomol. Struct. Dyn.2019381486510.1080/07391102.2019.1567388 30633630
     [Google Scholar]
  22. DebnathS. DebnathT. MajumdarS. KalleA. AparnaV. Identification of potent histone deacetylase 8 inhibitors using pharmacophore-based virtual screening, three-dimensional quantitative structure–activity relationship, and docking study.Res. Rep. Med. Chem.2015213910.2147/RRMC.S81388
     [Google Scholar]
  23. AminS.A. AdhikariN. JhaT. Structure-activity relationships of hydroxamate-based histone deacetylase-8 inhibitors: reality behind anticancer drug discovery.Future Med. Chem.20179182211223710.4155/fmc‑2017‑0130 29182018
     [Google Scholar]
  24. AminS.A. AdhikariN. JhaT. Structure-activity relationships of HDAC8 inhibitors: Non-hydroxamates as anticancer agents.Pharmacol. Res.201813113112814210.1016/j.phrs.2018.03.001 29514055
     [Google Scholar]
  25. BanerjeeS. AdhikariN. AminS.A. JhaT. Histone deacetylase 8 (HDAC8) and its inhibitors with selectivity to other isoforms: An overview.Eur. J. Med. Chem.201916421424010.1016/j.ejmech.2018.12.039 30594678
     [Google Scholar]
  26. CaoG.P. ThangapandianS. SonM. KumarR. ChoiY.J. KimY. KwonY.J. KimH.H. SuhJ.K. LeeK.W. QSAR modeling to design selective histone deacetylase 8 (HDAC8) inhibitors.Arch. Pharm. Res.201639101356136910.1007/s12272‑015‑0705‑5 27542119
     [Google Scholar]
  27. AminS.A. KhatunS. GayenS. DasS. JhaT. Are inhibitors of histone deacetylase 8 (HDAC8) effective in hematological cancers especially acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)?Eur. J. Med. Chem.202325811559410.1016/j.ejmech.2023.115594 37429084
     [Google Scholar]
  28. PiduguV.R. YarlaN.S. PedadaS.R. KalleA.M. SatyaA.K. Design and synthesis of novel HDAC8 inhibitory 2,5-disubstituted-1,3,4-oxadiazoles containing glycine and alanine hybrids with anti cancer activity.Bioorg. Med. Chem.201624215611561710.1016/j.bmc.2016.09.022 27665180
     [Google Scholar]
  29. WangD.F. WiestO. HelquistP. Lan-HargestH.Y. WiechN.L. On the function of the 14 Å long internal cavity of histone deacetylase-like protein: implications for the design of histone deacetylase inhibitors.J. Med. Chem.200447133409341710.1021/jm0498497 15189037
     [Google Scholar]
  30. KunzeM.B.A. WrightD.W. WerbeckN.D. KirkpatrickJ. CoveneyP.V. HansenD.F. Loop interactions and dynamics tune the enzymatic activity of the human histone deacetylase 8.J. Am. Chem. Soc.201313547178621786810.1021/ja408184x 24171457
     [Google Scholar]
  31. MillerT.A. WitterD.J. BelvedereS. Histone deacetylase inhibitors.J. Med. Chem.200346245097511610.1021/jm0303094 14613312
     [Google Scholar]
  32. KimS. LeeY. KimS. LeeS.J. HeoP.K. KimS. KwonY.J. LeeK.W. Identification of novel human HDAC8 inhibitors by pharmacophore‐based virtual screening and density functional theory approaches.Bull. Korean Chem. Soc.201839219720610.1002/bkcs.11366
     [Google Scholar]
  33. DebnathS. DebnathT. BhaumikS. MajumdarS. KalleA.M. AparnaV. Discovery of novel potential selective HDAC8 inhibitors by combine ligand-based, structure-based virtual screening and in-vitro biological evaluation.Sci. Rep.2019911717410.1038/s41598‑019‑53376‑y 31748509
     [Google Scholar]
  34. HouX. DuJ. LiuR. ZhouY. LiM. XuW. FangH. Enhancing the sensitivity of pharmacophore−based virtual screening by incorporating customized ZBG features: A case study using histone deacetylase 8.J. Chem. Inf. Model.201555486187110.1021/ci500762z 25757142
     [Google Scholar]
  35. SundarapandianT. ShaliniJ. SugunadeviS. WooL.K. Docking-enabled pharmacophore model for histone deacetylase 8 inhibitors and its application in anti-cancer drug discovery.J. Mol. Graph. Model.201029338239510.1016/j.jmgm.2010.07.007 20870437
     [Google Scholar]
  36. SodjiQ.H. PatilV. KornackiJ.R. MrksichM. OyelereA.K. Synthesis and structure-activity relationship of 3-hydroxypyridine-2-thione-based histone deacetylase inhibitors.J. Med. Chem.201356249969998110.1021/jm401225q 24304348
     [Google Scholar]
  37. PatilV. SodjiQ.H. KornackiJ.R. MrksichM. OyelereA.K. 3-Hydroxypyridin-2-thione as novel zinc binding group for selective histone deacetylase inhibition.J. Med. Chem.20135693492350610.1021/jm301769u 23547652
     [Google Scholar]
  38. JingQ. HuX. MaY. MuJ. LiuW. XuF. LiZ. BaiJ. HuaH. LiD. Marine-derived natural lead compound disulfide-linked dimer psammaplin a: biological activity and structural modification.Mar. Drugs201917738410.3390/md17070384 31252563
     [Google Scholar]
  39. PanH. CaoJ. XuW. Selective histone deacetylase inhibitors.Anticancer. Agents Med. Chem.201212324727010.2174/187152012800228814
     [Google Scholar]
  40. ZhangL. ZhangJ. JiangQ. ZhangL. SongW. Zinc binding groups for histone deacetylase inhibitors.J. Enzyme Inhib. Med. Chem.201833171472110.1080/14756366.2017.1417274 29616828
     [Google Scholar]
  41. VemaA. DebnathS. KalleA.M. Identification of novel HDAC8 selective inhibitors through ligand and structure based studies: Exploiting the acetate release channel differences among class I isoforms.Arab. J. Chem.202215610386310.1016/j.arabjc.2022.103863
     [Google Scholar]
  42. FreyR.R. CurtinM.L. GarlandR.B. WadaC.K. VasudevanA. MichaelidesM.R. Electrophilic ketone−based histone deacetylase (HDAC) inhibitors as cancer chemotherapeutic agents.Abstracts Papers Am. Chem. Soc.2002224U27
     [Google Scholar]
  43. ShenS. KozikowskiA.P. Why hydroxamates may not be the best histone deacetylase inhibitors—what some may have forgotten or would rather forget?ChemMedChem2016111152110.1002/cmdc.201500486 26603496
     [Google Scholar]
  44. JacobsenF.E. LewisJ.A. CohenS.M. A new role for old ligands: discerning chelators for zinc metalloproteinases.J. Am. Chem. Soc.2006128103156315710.1021/ja057957s 16522091
     [Google Scholar]
  45. EstiuG. WestN. MazitschekR. GreenbergE. BradnerJ.E. WiestO. On the inhibition of histone deacetylase 8.Bioorg. Med. Chem.201018114103411010.1016/j.bmc.2010.03.080 20472442
     [Google Scholar]
  46. WuR. WangS. ZhouN. CaoZ. ZhangY. A proton-shuttle reaction mechanism for histone deacetylase 8 and the catalytic role of metal ions.J. Am. Chem. Soc.2010132279471947910.1021/ja103932d 20568751
     [Google Scholar]
  47. VaidyaA.S. NeelarapuR. MadriagaA. BaiH. MendoncaE. AbdelkarimH. van BreemenR.B. BlondS.Y. PetukhovP.A. Novel histone deacetylase 8 ligands without a zinc chelating group: Exploring an ‘upside-down’ binding pose.Bioorg. Med. Chem. Lett.201222216621662710.1016/j.bmcl.2012.08.104 23010266
     [Google Scholar]
  48. HaiderS. JosephC.G. NeidleS. FierkeC.A. FuchterM.J. On the function of the internal cavity of histone deacetylase protein 8: R37 is a crucial residue for catalysis.Bioorg. Med. Chem. Lett.20112172129213210.1016/j.bmcl.2011.01.128 21320778
     [Google Scholar]
/content/journals/mc/10.2174/0115734064320232240709105228
Loading
Crucial Structural Understanding for Selective HDAC8 Inhibition: Common Pharmacophores, Molecular Docking, Molecular Dynamics, and Zinc Binder Analysis of Selective HDAC8 Inhibitors
Med. Chem. 21, 597 (2025); https://doi.org/10.2174/0115734064320232240709105228
/content/journals/mc/10.2174/0115734064320232240709105228
/content/journals/mc/10.2174/0115734064320232240709105228
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Review Article
Keyword(s): common pharmacophores; crucial interactions; molecular docking; molecular dynamics; selective HDAC8 inhibitors; Structural insights of HDACs

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test