Background: The altered expression of histone deacetylase family member 8 (HDAC8) has been found to be linked with various cancers, thereby making its selective inhibition a potential strategy in cancer therapy. Recently, plant secondary metabolites, particularly phenolic compounds, have been shown to possess HDAC inhibitory activity.
Objective: In the present work, we have evaluated the potential of cinnamaldehyde (CAL), cinnamic acid (CA), and cinnamyl alcohol (CALC) (bioactives of Cinnamomum) as well as aqueous cinnamon extract (ACE), to inhibit HDAC8 activity in vitro and in silico.
Materials and methods: HDAC8 inhibitory activity of ACE and cinnamon bioactives was determined in vitro using HDAC8 inhibitor screening kit. Trichostatin A (TSA), a well-known anti-cancer agent and HDAC inhibitor, was used as a positive control. In silico studies included molecular descriptor Analysis molecular docking absorption, distribution, metabolism, excretion, and toxicity prediction, density function theory calculation and synthetic accessibility program.
Results: Pharmacoinformatics studies implicated that ACE and its Bioactives (CAL, CA, and CALC) exhibited comparable activity with that of TSA. The highest occupied molecular orbitals and lowest unoccupied molecular orbitals along with binding energy of cinnamon bioactives were comparable with that of TSA. Molecular docking results suggested that all the ligands maintained two hydrogen bond interactions within the active site of HDAC8. Finally, the synthetic accessibility values showed that cinnamon bioactives were easy to synthesize compared to TSA.
Conclusion: It was evident from both the experimental and computational data that cinnamon bioactives exhibited significant HDAC8 inhibitory activity, thereby suggesting their potential therapeutic implications against cancer.
Summary: Pharmacoinformatics studies revealed that cinnamon bioactives bound to the active site of HDAC8 enzyme in a way similar to that of TSAThe molecular descriptors of cinnamon compounds successfully correlated with TSA values. The binding interactions and energies were also found to be close to TSASynthetic accessibility values showed that cinnamon bioactives were easy to synthesize compared to TSA. Abbreviations used: ACE: Aqueous Cinnamon Extract; DFT: Density Function Theory; CAL: Cinnamaldehyde; CA: Cinnamic Acid; CALC: Cinnamyl Alcohol; MW: Molecular Weight; ROTBs: Rotatable Bonds; ROF: Lipinski's Rule of Five; TSA: Trichostatin A; PDB: Protein Data Bank; RMSD: Root Mean Square Deviation; HBA: Hydrogen Bond Acceptor; HBD: Hydrogen Bond Donor; ADMET: Absorption, Distribution, Metabolism, Excretion and Toxicity; FO: Frontier Orbital; HOMOs: Highest Occupied Molecular Orbitals; LUMOs: Lowest Unoccupied Molecular Orbitals; BE: Binding Energy.
Keywords: Absorption; HDAC8; cinnamon; density function theory; distribution; excretion; metabolism; molecular docking; synthetic accessibility; toxicity prediction.