Docking, Binding Free Energy Calculations and In Vitro Characterization of Pyrazine Linked 2-Aminobenzamides as Novel Class I Histone Deacetylase (HDAC) Inhibitors
Emre F. Bülbül,
Jelena Melesina,
Hany S. Ibrahim,
Mohamed Abdelsalam,
Anita Vecchio,
Dina Robaa,
Matthes Zessin,
Mike Schutkowski,
Wolfgang Sippl
Affiliations
Emre F. Bülbül
Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), Germany
Jelena Melesina
Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), Germany
Hany S. Ibrahim
Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), Germany
Mohamed Abdelsalam
Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), Germany
Anita Vecchio
Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), Germany
Dina Robaa
Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), Germany
Matthes Zessin
Department of Enzymology, Institute of Biochemistry and Biotechnology, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany
Mike Schutkowski
Department of Enzymology, Institute of Biochemistry and Biotechnology, Martin-Luther-University of Halle-Wittenberg, 06120 Halle (Saale), Germany
Wolfgang Sippl
Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), Germany
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.
