Browsing by Author "Elmezayen, Ammar Dawoud Ahmed Mahmoud"

Now showing 1 - 1 of 1

In silico designing of isoform-selective inhibitors against class IIA histone deacetylases
(Kadir Has Üniversitesi, 2021) Elmezayen, Ammar Dawoud Ahmed Mahmoud; Yelekçi, Kemal
The fundamental cause of human cancer is strongly influenced by down- or upregulations 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. Constant Search for specific HDAC isoform inhibitors is increasingly developing to avoid this side effect. 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 study was to examine the similarity of class IIa HDACs (4, 5, 7, and 9) by aligning their structures and amino acid sequences, active site extraction, and recognition of the key amino acid residues within the catalytic channel. X-ray crystal structure of the human HDAC4 was used as a template for homology modeling of human HDACs 5 and 9. Consequently, isoform-selective inhibitors against class IIa HDACs were identified via structure- and ligand-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 towards 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.