Application of Ligand- and Structure-Based Prediction Models for the Design of Alkylhydrazide-Based HDAC3 Inhibitors as Novel Anti-Cancer Compounds.
Emre F Bülbül, Dina Robaa, Ping Sun, Fereshteh Mahmoudi, Jelena Melesina, Matthes Zessin, Mike Schutkowski, Wolfgang Sippl
Author Information
Emre F Bülbül: Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), Germany. ORCID
Dina Robaa: Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), Germany.
Ping Sun: Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), Germany. ORCID
Fereshteh Mahmoudi: 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.
Matthes Zessin: Department of Enzymology, Institute of Biotechnology, Martin-Luther University of Halle-Wittenberg, 06120 Halle (Saale), Germany.
Mike Schutkowski: Department of Enzymology, Institute of 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. ORCID
Histone deacetylases (HDAC) represent promising epigenetic targets for several diseases including different cancer types. The HDAC inhibitors approved to date are pan-HDAC inhibitors and most show a poor selectivity profile, side effects, and in particular hydroxamic-acid-based inhibitors lack good pharmacokinetic profiles. Therefore, the development of isoform-selective non-hydroxamic acid HDAC inhibitors is a highly regarded field in medicinal chemistry. In this study, we analyzed different ligand-based and structure-based drug design techniques to predict the binding mode and inhibitory activity of recently developed alkylhydrazide HDAC inhibitors. Alkylhydrazides have recently attracted more attention as they have shown promising effects in various cancer cell lines. In this work, pharmacophore models and atom-based quantitative structure-activity relationship (QSAR) models were generated and evaluated. The binding mode of the studied compounds was determined using molecular docking as well as molecular dynamics simulations and compared with known crystal structures. Calculated free energies of binding were also considered to generate QSAR models. The created models show a good explanation of in vitro data and were used to develop novel HDAC3 inhibitors.
