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Updated: Dec 2, 2025
Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
Cracking a cancer code histone deacetylation in epigenetic: the implication from molecular dynamics simulations on
Ramachandren Dushanan1, Samantha Weerasinghe2, Dhammike P Dissanayake2
1Department of Chemistry, Faculty of Natural Sciences, The Open University of Sri Lanka, Nugegoda, Sri Lanka.
Abstract:
Epigenetic changes, histone acetylation and deacetylation in chromatin have been intensively studied due to their significance in regulating the gene expression. According to the type of tumor, the levels of histone deacetylases (HDAC) are varied. HDAC inhibitors are a new promising class of compounds that inhibit the proliferation of tumor cells. In this study, the inhibitory efficacy of some HDAC inhibitors such as vorinostat, panobinostat, abexinostat, belinostat, resminostat, dacinostat and pracinostat was studied using molecular dynamics simulation. The inhibitory efficacy was estimated by computing the enzyme's stability, positional stability of the individual amino acids and interaction energies of HDLP-inhibitor complexes. It is hoped that this investigation may improve our understanding of the atomic-level description of the inhibitor binding site and how the HDAC inhibitors change the environment of the enzyme's active site. The results obtained from the root-mean-square deviation, the radius of gyration, solvent-accessible surface area, root-mean-square fluctuation, stride server and Ramachandran plot have revealed that the stability of HDLP enzyme with vorinostat, panobinostat and abexinostat is higher than the other studied complexes. According to the calculated values for MM-PBSA, LIE, semi-LIE binding free energies and interaction energies, the stability of the HDLP enzyme varies as panobinostat > abexinostat > vorinostat where resminostat complex showed relatively low stability. The ligandability and drugability values also give the same trend as above. The findings revealed that the panobinostat and abexinostat are potential lead compounds as reference inhibitor vorinostat. Therefore, it is possible to use these drugs as HDAC inhibitors in clinical practices. Also, the outcomes of this study could be utilized to identify new inhibitors for clinical research.Communicated by Ramaswamy H. Sarma.
Insights
Histone deacetylase (HDAC) inhibitors like panobinostat and abexinostat show high efficacy in blocking tumor cell proliferation. Molecular dynamics simulations reveal their superior stability and potential as lead compounds for cancer therapy.
Area of Science:
- Biochemistry and Molecular Biology
- Pharmacology and Toxicology
- Computational Chemistry
Background:
- Epigenetic modifications, including histone acetylation and deacetylation, play a crucial role in gene expression regulation.
- Histone deacetylases (HDACs) are implicated in various tumor types, making HDAC inhibitors a promising therapeutic strategy.
- Understanding the atomic-level interactions of HDAC inhibitors is vital for developing effective cancer treatments.
Purpose of the Study:
- To evaluate the inhibitory efficacy of several HDAC inhibitors against the HDLP enzyme using molecular dynamics simulations.
- To analyze the stability and binding interactions of HDAC inhibitor-enzyme complexes at the atomic level.
- To identify potential lead compounds for novel HDAC inhibitor development.
Main Methods:
- Molecular dynamics simulations were employed to study HDAC inhibitors: vorinostat, panobinostat, abexinostat, belinostat, resminostat, dacinostat, and pracinostat.
- Enzyme stability, amino acid positional stability, and HDLP-enzyme inhibitor interaction energies were computed.
- Analysis included root-mean-square deviation, radius of gyration, solvent-accessible surface area, root-mean-square fluctuation, and Ramachandran plots.
Main Results:
- Vorinostat, panobinostat, and abexinostat demonstrated higher HDLP enzyme stability compared to other inhibitors.
- Binding free energy calculations (MM-PBSA, LIE, semi-LIE) indicated a stability order of panobinostat > abexinostat > vorinostat.
- Panobinostat and abexinostat emerged as potent lead compounds, exhibiting favorable ligandability and drugability profiles.
Conclusions:
- Panobinostat and abexinostat show significant potential as HDAC inhibitors, comparable to or exceeding the efficacy of vorinostat.
- These findings support the use of panobinostat and abexinostat in clinical settings for cancer treatment.
- The study provides insights for the rational design of new HDAC inhibitors for future clinical research.
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