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

doi:10.20944/preprints202305.1124.v1

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preprints.org > biology and life sciences > life sciences > doi: 10.20944/preprints202305.1124.v1

Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Application of Ligand- and Structure-Based Prediction Models for the Design of Alkylhydrazide-Based HDAC3 Inhibitors as Novel Anti-cancer Compounds

Version 1 : Received: 16 May 2023 / Approved: 16 May 2023 / Online: 16 May 2023 (08:26:45 CEST)

A peer-reviewed article of this Preprint also exists.

Bülbül, E.F.; Robaa, D.; Sun, P.; Mahmoudi, F.; Melesina, J.; Zessin, M.; Schutkowski, M.; Sippl, W. Application of Ligand- and Structure-Based Prediction Models for the Design of Alkylhydrazide-Based HDAC3 Inhibitors as Novel Anti-Cancer Compounds. Pharmaceuticals 2023, 16, 968. Bülbül, E.F.; Robaa, D.; Sun, P.; Mahmoudi, F.; Melesina, J.; Zessin, M.; Schutkowski, M.; Sippl, W. Application of Ligand- and Structure-Based Prediction Models for the Design of Alkylhydrazide-Based HDAC3 Inhibitors as Novel Anti-Cancer Compounds. Pharmaceuticals 2023, 16, 968.

Abstract

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 especially 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 models created show a good explanation of in vitro data and were used to develop novel HDAC3 inhibitors.

Keywords

docking; binding free energy; pharmacophore; KPLS; QSAR; alkylhydrazide; histone deacetylases (HDAC)

Subject

Biology and Life Sciences, Life Sciences

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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