Investigating Potential Cancer Therapeutics: Insight into Histone Deacetylases (HDACs) Inhibitions

Abstract

Histone deacetylases (HDACs) are enzymes that remove acetyl groups from ɛ-amino of histone, and their involvement in the development and progression of cancer disorders makes them an interesting therapeutic target. This study seeks to discover new inhibitors that selectively inhibit HDAC enzymes which are linked to deadly disorders like T-cell lymphoma, childhood neuroblastoma, and colon cancer. MOE was used to dock libraries of ZINC database molecules within the catalytic active pocket of target HDACs. The top three hits were submitted to MD simulations ranked on binding affinities and well-occupied interaction mechanisms determined from molecular docking studies. Inside the catalytic active site of HDACs, the two stable inhibitors LIG1 and LIG2 affect the protein flexibility, as evidenced by RMSD, RMSF, Rg, and PCA. MD simulations of HDACs complexes revealed an alteration from extended to bent motional changes within loop regions. The structural deviation following superimposition shows flexibility via a visual inspection of movable loops at different timeframes. According to PCA, the activity of HDACs inhibitors induces structural dynamics that might potentially be utilized to define the nature of protein inhibition. The findings suggest that this study offers solid proof to investigate LIG1 and LIG2 as potential HDAC inhibitors.

Keywords: histone deacetylases; molecular docking; molecular dynamic simulation; neuroblastoma.

Figure 1

Structures of selective HDACIs. (A) Superimposition of HDACs’ catalytic site residues stabilize Zn²⁺ via metal coordinating bonds. (B) Surface mapping and superimposition of HDAC2 bound with crystalized structure and docked structure. In both panels, the residues within the catalytic site of HDACs were depicted in sticks. The solved crystal complex (7LTG) and docked apicidin in this work were colored yellow and blue, respectively. Residues in the active site D100, H141, H142, D177, H179, D265, and Y304 were also labeled. The Zn²⁺ ions are represented as spheres in the catalytic site of each complex that are involved in the coordination with apicidin and binding residues. Moreover, in both the panels, the hydrogen bonds and metal coordination bonds were shown as yellow, blue, magenta, and green dashes, respectively.

Figure 2

Chemical structures of the hit molecules based on binding S-score and interaction pattern.

Figure 3

Structures of selective HDACs in complex with LIG1 (red), LIG2 (orange), and LIG3 (cyan). (A) Superimposition of HDAC1, 2, and 3 structures bound with LIG1, LIG2, and LIG3 in the catalytic site; (B) hydrophobicity surface showing that the inhibitors are bound deep in the hydrophobic pocket; (C) superimposition of HDAC1, 2, and 3 structures shows the interaction pattern bound with LIG1, LIG2, and LIG3. In all three panels, the residues and inhibitors at the hydrophobic active pocket were shown as ball and stick models. The Zn²⁺ ions at the active site of HDAC1, 2, and 3 that are involved in hydrogen bonding were shown as spheres. Coordination bonds and hydrogen bonds LIG1, LIG2, and LIG3 with their respective HDAC were shown as red, magenta, and yellow dashed lines, respectively.

Figure 4

Comparison changes in RMSD values, Rg values, and intermolecular H bonds; (A) Rmsd deviations of LIG1-bound HDACs complexes, (B) Rmsd deviations of LIG2-bound HDACs complex, (C) Rg compactness of LIG1- and LIG2-bound HDACs complexes, (D) hydrogen bonds analysis of LIG1- and LIG2-bound HDACs complexes.

Figure 5

Root mean square fluctuation (RMSF) values of solvated HDAC enzymes bound with LIG1 and LIG2 were plotted versus residue number.

Figure 6

Structural mobility of and conformational changes in HDACs enzymes during 100 ns of the simulation system.

Figure 7

Comparison changes in PCA pattern of HDACs interactions with different LIG1 and LIG2; (A) LIG1−HDAC1 complex, (B) LIG1−HDAC2 complex, (C) LIG1−HDAC3 complex, (D) LIG2− HDAC1 complex, (E) LIG2−HDAC2 complex, and (F) LIG2−HDAC3 complex.

Figure 8

The FEL plots for the ligand-bound HDACs complexes. (A) LIG1-HDAC1 complex, (B) LIG1-HDAC2 complex, (C) LIG1-HDAC3 complex, (D) LIG2-HDAC1 complex, (E) LIG2-HDAC2 complex, and (F) LIG2-HDAC3 complex.

Figure 9

Plots of HDACs dynamic cross-correlation. (A) LIG1-HDAC1 complex, (B) LIG1-HDAC2 complex, (C) LIG1-HDAC3 complex, (D) LIG2-HDAC1 complex, (E) LIG2-HDAC2 complex, and (F) LIG2-HDAC3 complex. The coloring changes from pink (−), white (0), and cyan (+). The negative value shows anti-correlation, which means the atoms are moving in the opposite direction, while the positive value shows correlated mobility, which means atoms are moving in the same direction.

Figure 10

Structural imposition at 0 ns and 100 ns timeframe. (A) LIG1-HDAC1, (B) LIG1-HDAC2, (C) LIG1-HDAC3, (D) LIG2-HDAC1, (E) LIG2-HDAC2, and (F) LIG2-HDAC3. The dotted circle represents the ligand binding site.

Figure 11

Evaluation of ligands’ permeability through the gastrointestinal tract and brain by BOILED-Egg method.