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. 2022 May 24;7(22):18786-18794.
doi: 10.1021/acsomega.2c01572. eCollection 2022 Jun 7.

Discovery of Histone Deacetylase Inhibitor Using Molecular Modeling and Free Energy Calculations

Abha Mishra  1 , Amit Singh  2
Affiliations

Discovery of Histone Deacetylase Inhibitor Using Molecular Modeling and Free Energy Calculations

Abha Mishra et al. ACS Omega. .

Abstract

The histone acetylation-deacetylation at lysine regulates the functions of many cellular proteins. An increased expression of HDAC6 can cause an increased amount of deacetylated histones, which leads to an inhibition of gene expression and has been associated with cancer cell proliferation. The present study screened the ZINC database to find novel HDAC6 inhibitors using virtual high-throughput screening techniques. The docking score, free energy, and binding pattern of the complexes were used to select a best ligand for further study. Molecular dynamic simulations, binding interactions, and the stability of docked conformations were investigated. Several parameters that determine protein-ligand interactions, such as root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), and binding pattern, were observed. Hydrogen bonds were observed at His 573 and Gly 582 after a 150 ns simulation with identified compound ZINC000002845205, and they were similar to known inhibitor Panobinostat. The molecular mechanics with generalised Born and surface area solvation (MM/GBSA) free energy was comparable to known inhibitor Panobinostat. ZINC000002845205 qualifies drug-likeness according to Lipinski's rule-of-five, rule-of-three, and the World Drug Index (WDI)-like rule, but there is one violation in the lead-like rule.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Molecular docking of (a) HDAC6 with Panobinostat [6918837] and (b) HDAC6 with ZINC000002845205.
Figure 2
Figure 2
RMSD profile of HDAC6 during 150 ns MD simulation (blue, HDAC6; orange, HDAC6 + Panobinostat; gray, HDAC6 + ZINC compound).
Figure 3
Figure 3
RMSD profile of Panobinostat and ZINC compound during 150 ns MD simulation (blue, Panobinostat; orange, ZINC compound).
Figure 4
Figure 4
RMSF study to show local changes around the protein chain (blue, HDAC6; orange, HDAC6 + Panobinostat; gray, HDAC6 + ZINC compound).
Figure 5
Figure 5
Compactness of the protein in terms of radius of gyration (Rg) during 150 ns MD simulation (blue, HDAC6; orange, HDAC6 + Panobinostat; gray, HDAC6 + ZINC compound).
Figure 6
Figure 6
H-bond formation between HDAC6 + Panobinostat during 150 ns MD simulation study.
Figure 7
Figure 7
A 2D schematic of ligand protein contacts (HDAC6 + Panobinostat) during 150 ns MD simulation study.
Figure 8
Figure 8
H-bond formation between HDAC6 + ZINC compound during 150 ns MD simulation study.
Figure 9
Figure 9
A 2D schematic of protein ligand contacts (HDAC6 + ZINC compound) during 150 ns MD simulation study.
Figure 10
Figure 10
HDAC6 + Panobinostat interaction during 150 ns simulation (water bridges, blue; H-bond, green; hydrophobic contacts, violet).
Figure 11
Figure 11
Top block shows specific contacts, and the bottom block displays HDAC6 + Panobinostat interactions during 150 ns simulation (dark orange shade represents a stable interaction).
Figure 12
Figure 12
HDAC6 + ZINC compound interactions during 150 ns simulation (water bridges, blue; H-bond, green; hydrophobic contacts, violet).
Figure 13
Figure 13
Top block shows specific contacts, and the bottom block displays HDAC6 + ZINC compound interactions during 150 ns simulation (dark orange shade represents a stable interaction).
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