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Histone deacetylase (HDAC) enzymes modify the histone by removing the acetyl group from the lysine residues, known as histone deacetylation. HDACs have been involved in altering gene expressions, resulting in cancer cells in the body. This study focuses on HDAC inhibitors’ impact on histone deacetylase-like protein (HDLP) stability through computational techniques. Molecular dynamics (MD) analyses were used to examine the atomic-level description of drug binding sites and how the HDAC inhibitors change the HDLP enzyme environment. In this study, two hydroxamic acid-derived inhibitors, such as [Formula: see text]-Carboxycinnamic acid bis-hydroxamide (CBHA) and scriptaid (GCK1026), were selected to examine the inhibition ability in terms with suberanilohydroxamic acid (SAHA) as a reference drug. The crystal structure of the HDLP was downloaded from the Protein Data Bank. The structures of inhibitors were optimized using the G09W package. Docking studies were done by AutoDock-Vina, and the resultant complex was used to initiate MD studies. The trajectories obtained from MD simulation were used to perform the structural analysis. Root-mean-square deviation (RMSD), radius of gyration, hydrogen bond, binding free energy and interaction energy studies revealed that the stability of HDLP-SAHA and HDLP-CBHA is higher than the free HDLP enzyme. The HDLP-CBHA complex shows an increased number of hydrogen bonds (5), high MM-PBSA binding free energy ([Formula: see text][Formula: see text]kJ/mol), high interaction energy ([Formula: see text][Formula: see text]kJ/mol), and an increased number of alpha-helical amino acids (130) compared with HDLP-SAHA. It concluded that the CBHA has the relatively same potential as SAHA to inhibit the HDLP. Consequently, the use of CBHA in clinical application is recommended through this in-silico method.

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Histone deacetylase (HDAC) is an enzyme that deacetylates the histone protein by removing the acetyl group from the lysine residues. The over-expression of the HDAC enzyme alters the gene expressions and causes cancer development in the human body. The inhibition of HDAC is an excellent therapeutic way in current cancer therapy. In this regard, various inhibitors were selected, and the inhibitory potential of these inhibitors was examined by molecular dynamics (MD) simulation followed by trajectory analysis and binding energy calculations. The selected clinical trial II and III phase inhibitors are TSA (trichostatin-A), TFMK (trifluoromethyl-ketone-9,9,9-trifluoro-8-oxo-N-phenylnonanamide), AKA (alpha-ketoamide-N-cyclohexyl-N-methyl-2-oxononanediamide), ITF2357 (givinostat), MS275 (entinostat), CI994 (tacedinaline), and SAHA (suberoylanilide hydroxamic acid). This computational study examines the atomic level description of the drug binding site on the HDLP enzyme and investigates the interaction of the HDAC inhibitors with the amino acid residues attached to the active site of the histone deacetylase-like protein (HDLP). Root-mean-square deviation, radius of gyration, hydrogen bond analysis, MM-PBSA, LIE, and semi-LIE calculations have revealed that the HDLP enzyme is more stabilized when bound to TSA, ITF2357, and reference inhibitor SAHA. It was observed that the hydroxamic acid family inhibitors have more potent in inhibiting the HDLP enzyme than the benzamide and ketone families. The inhibitory efficacy of TSA and ITF2357 is much similar to that of SAHA. Therefore, these HDAC inhibitors have the potential to be used in future clinical practices for cancer-related treatments. The knowledge gathered from this study could also lead to discovering new HDAC inhibitors for clinical research.