Related Experiment Video
Updated: Feb 2, 2026
Single-Step Enrichment of a TAP-Tagged Histone Deacetylase of the Filamentous Fungus Aspergillus nidulans for Enzymatic Activity Assay
Published on: May 1, 2019
Pharmacophore-based virtual screening for identification of potential selective inhibitors of human histone
Abdullahi Ibrahim Uba1, Kemal Yelekçi2
1Department of Bioinformatics and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University, 34083 Fatih, Istanbul, Turkey; Centre for Biotechnology Research, Bayero University, P.M.B 3011, B.U.K road, Kano, Nigeria.
Abstract:
Histone deacetylase (HDAC) 6 plays a role in oncogenic transformation and cancer metastasis via tubulin deacetylation, making it a critical target for anticancer drug design. However, lack of selectivity shown by many of the current HDAC6 inhibitors in clinical use and trials prompts the continuous search for selective inhibitors. Here, 10 pharmacophore hypotheses were developed based on the 3D common features of training set of 20 HDAC inhibitors in clinical use and trials. The hypotheses were validated using a test set of another 20 HDAC inhibitors along with 400 inactive (decoys) molecules based on Güner-Henry pharmacophore scoring method. Hypothesis 1 consisting of 1 H-bond donor, 1 H-bond acceptor and 2 hydrophobic features, was used to screen "DruglikeDiverse" database using Biovia Discovery Studio 4.5. The top 10 hit compounds were selected based on the pharmacophore fit values (>3.00). Their binding affinity against HDAC6 compared to class I HDACs (1, 2, 3 & 8) and a class IIa member (HDAC7), was calculated by molecular docking using AutoDock4. The stability of binding modes of 2 potential HDAC6-selective inhibitors (ENA501965 and IBS399024) was examined by 30 ns-molecular dynamics (MD) simulation using nanoscale MD (NAMD) software. Both ligands showed potential stability in HDAC6 active site over time. Therefore, these may provide additional scaffolds for further optimization towards the design of safe, potent and selective HDAC6 inhibitors.
Insights
Researchers developed new selective inhibitors for Histone deacetylase (HDAC) 6, a key target in cancer. Computational methods identified promising drug candidates, ENA501965 and IBS399024, showing stability and potential for developing safer, more effective cancer therapies.
Area of Science:
- Medicinal Chemistry
- Computational Drug Design
- Oncology
Background:
- Histone deacetylase (HDAC) 6 is implicated in cancer progression and metastasis.
- Current HDAC6 inhibitors lack selectivity, necessitating the development of novel agents.
- Targeting HDAC6 offers a promising strategy for anticancer drug development.
Purpose of the Study:
- To design and identify novel, selective HDAC6 inhibitors.
- To develop pharmacophore hypotheses for HDAC6 inhibitors.
- To screen for potential drug candidates with improved selectivity and efficacy.
Main Methods:
- Development and validation of 10 pharmacophore hypotheses.
- Screening of the DruglikeDiverse database using Biovia Discovery Studio 4.5.
- Molecular docking and 30 ns molecular dynamics simulations to assess binding affinity and stability.
Main Results:
- Hypothesis 1, featuring specific H-bond donor, acceptor, and hydrophobic features, was selected.
- Ten hit compounds were identified, with ENA501965 and IBS399024 showing high binding affinity and stability.
- These compounds demonstrated potential selectivity for HDAC6 over other HDAC classes.
Conclusions:
- The identified compounds, ENA501965 and IBS399024, represent promising scaffolds for developing selective HDAC6 inhibitors.
- Further optimization of these compounds could lead to safer and more potent anticancer drugs.
- This study provides a foundation for the rational design of next-generation HDAC6-targeted cancer therapies.
Related Concept Videos
02:32Histone Modification
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone...
02:32Histone Modification
01:52Eukaryotic Transcription Inhibitors
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
02:30Histone Variants at the Centromere
01:20Virtual Work
In static equilibrium, a body can experience an imaginary or virtual movement, such as displacement or rotation. The virtual work done by a force is equal to the dot product of force and virtual displacement in the direction of the force. When it comes to virtually rotating a...
01:13Principle of Virtual Work: Problem Solving
To apply the principle of virtual work,...