Docking, Binding Free Energy Calculations and In Vitro Characterization of Pyrazine Linked 2-Aminobenzamides as Novel Class I Histone Deacetylase (HDAC) Inhibitors.

Abstract

Class I histone deacetylases, HDAC1, HDAC2, and HDAC3, represent potential targets for cancer treatment. However, the development of isoform-selective drugs for these enzymes remains challenging due to their high sequence and structural similarity. In the current study, we applied a computational approach to predict the selectivity profile of developed inhibitors. Molecular docking followed by MD simulation and calculation of binding free energy was performed for a dataset of 2-aminobenzamides comprising 30 previously developed inhibitors. For each HDAC isoform, a significant correlation was found between the binding free energy values and in vitro inhibitory activities. The predictive accuracy and reliability of the best preforming models were assessed on an external test set of newly designed and synthesized inhibitors. The developed binding free-energy models are cost-effective methods and help to reduce the time required to prioritize compounds for further studies.

• Authors: Emre F Bülbül, Jelena Melesina, Hany S Ibrahim, Mohamed Abdelsalam, Anita Vecchio, Dina Robaa, Matthes Zessin, Mike Schutkowski, Wolfgang Sippl
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 27 Issue 8 (Apr 14 2022) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 35458724 (Publication Type: Journal Article)

Chemical References

• Histone Deacetylase Inhibitors
• Protein Isoforms
• Pyrazines
• Histone Deacetylase 1
• Histone Deacetylase 2
• Histone Deacetylases

Topics

• Histone Deacetylase 1
• Histone Deacetylase 2
• Histone Deacetylase Inhibitors (chemistry, pharmacology)
• Histone Deacetylases (metabolism)
• Molecular Docking Simulation
• Protein Isoforms
• Pyrazines (chemistry)
• Reproducibility of Results