AnIn-SilicoApproach to Evaluate the Inhibitory Potency of Selected Hydroxamic Acid Derivatives on Zinc-Dependent Histone Deacetylase Enzyme

Abstract

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.

Electrostatics in Computational Biophysics and Its Implications for Disease Effects

“…The result showed that the stability of HDLP–CBHA (m-Carboxycinnamic acid bis-hydroxide (CBHA)) is higher than that of the free HDLP enzyme. The higher stability was contributed by the increased number of hydrogen bonds [ 15 ]. Similarly, computational modeling of a prospective drug, dorzagliatin, showed it interacting with human glucokinase activator (GKA).…”

“…Molecular dynamics and MMPBSA methods were also used to probe the effect of inhibitors. This was done in the case of histone deacetylase-like proteins, and showed that affinity increases with the increase in hydrogen bonds [ 15 ]. Similarly, inhibitors against cyclin G-associated kinase involved in hepatitis C virus entry into host cells were studied, and short-range interactions were analyzed [ 34 ].…”

“…Short-range interactions, including salt bridges and hydrogen bonds, which are favorable interactions in terms of Coulombic energy, are present inside/among the macromolecules, serving as an important feature contributing to macromolecular architecture. Short-range effects frequently contribute to receptor–ligand binding [ 14 , 15 ] and to the specificity of the binding mode [ 16 , 17 ]. The pH-optimum is the particular pH at which biological activity, macromolecular stability, and binding are best optimized [ 18 ].…”

Exploration of Novel Mono Hydroxamic Acid Derivatives as Inhibitors for Histone Deacetylase Like Protein (HDLP) by Molecular Dynamics Studies

“…The acetylation of lysine residues found in the N terminal of core histone is one of the post-translational chromatin modifications that affect gene expression [6]. Acetylation and deacetylation of histones are restricted by the enzymes of histone acetyltransferase and histone deacetylase (HDACs) [7]. Alterations of gene expression are a hallmark of cancer, and evidence suggests an epigenetic mechanism mediates at fewest a component of these alterations [8].…”