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Updated: Nov 7, 2025
Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
Structure-based virtual screening for novel potential selective inhibitors of class IIa histone deacetylases for
Ammar D Elmezayen1, Yelekçi Kemal1
1Department of Bioinformatics and Genetics, Faculty of Engineering and Natural Sciences, Kadir Has University, 34083, Cibali, Istanbul, Turkey.
Abstract:
The fundamental cause of human cancer is strongly influenced by down- or up-regulations of epigenetic factors. Upregulated histone deacetylases (HDAC) have been shown to be effectively neutralized by the action of HDACs inhibitors (HDACi). However, cytotoxicity has been reported in normal cells because of non-specificity of several available HDACis that are in clinical use or at different phases of clinical trials. Because of the high amino acid sequence and structural similarity among HDAC enzymes, it is believed to be a challenging task to obtain isoform-selectivity. The essential aim of the present research work was to identify isoform-selective inhibitors against class IIa HDACs via structure-based drug design. Based on the highest binding affinity and isoform-selectivity, the top-ranked inhibitors were in silico tested for their absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties, which were classified as drug-like compounds. Later, molecular dynamics simulation (MD) was carried out for all compound-protein complexes to evaluate the structural stability and the biding mode of the inhibitors, which showed high stability throughout the 100 ns simulation. Free binding energy predictions by MM-PBSA method showed the high binding affinity of the identified compounds toward their respective targets. Hence, these inhibitors could be used as drug candidates or as lead compounds for more in silico or in vitro optimization to design safe isoform-selective HDACs inhibitors.
Insights
Researchers developed novel isoform-selective histone deacetylase inhibitors (HDACi) for cancer therapy. These drug-like compounds show high binding affinity and stability, offering a safer alternative to current treatments by targeting specific cancer-related HDACs.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Epigenetic factors, particularly histone deacetylases (HDACs), play a crucial role in human cancer development.
- Current HDAC inhibitors (HDACi) often lack isoform-selectivity, leading to cytotoxicity in normal cells.
- Developing isoform-selective HDAC inhibitors is challenging due to high structural similarity among HDAC enzymes.
Purpose of the Study:
- To identify isoform-selective inhibitors targeting class IIa HDACs using structure-based drug design.
- To evaluate the drug-like properties and binding stability of potential inhibitors.
Main Methods:
- Structure-based drug design was employed to identify inhibitors.
- In silico analysis included ADMET property prediction and molecular dynamics (MD) simulations.
- MM-PBSA method was used for free binding energy calculations.
Main Results:
- Top-ranked inhibitors demonstrated high binding affinity and isoform-selectivity for class IIa HDACs.
- In silico ADMET profiling classified the compounds as drug-like.
- MD simulations confirmed the structural stability of inhibitor-protein complexes over 100 ns.
- MM-PBSA analysis indicated strong binding affinities.
Conclusions:
- The identified compounds are promising drug candidates or lead structures for developing safer, isoform-selective HDAC inhibitors.
- Further in silico and in vitro optimization can lead to novel therapeutic agents for cancer treatment.
