Identification of novel leads as potent inhibitors of HDAC3 using ligand-based pharmacophore modeling and MD simulation

Abstract

In the landscape of epigenetic regulation, histone deacetylase 3 (HDAC3) has emerged as a prominent therapeutic target for the design and development of candidate drugs against various types of cancers and other human disorders. Herein, we have performed ligand-based pharmacophore modeling, virtual screening, molecular docking, and MD simulations to design potent and selective inhibitors against HDAC3. The predicted best pharmacophore model ‘Hypo 1’ showed excellent correlation (R2 = 0.994), lowest RMSD (0.373), lowest total cost value (102.519), and highest cost difference (124.08). Hypo 1 consists of four salient pharmacophore features viz. one hydrogen bond acceptor (HBA), one ring aromatic (RA), and two hydrophobic (HYP). Hypo 1 was validated by Fischer's randomization with a 95% of confidence level and the external test set of 60 compounds with a good correlation coefficient (R2 = 0.970). The virtual screening of chemical databases, drug-like properties calculations followed by molecular docking resulted in identifying 22 representative hit compounds. Performed 50 ns of MD simulations on top three hits were retained the salient π-stacking, Zn2+ coordination, hydrogen bonding, and hydrophobic interactions with catalytic residues from the active site pocket of HDAC3. Total binding energy calculated by MM-PBSA showed that the Hit 1 and Hit 2 formed stable complexes with HDAC3 as compared to reference TSA. Further, the PLIP analysis showed a close resemblance between the salient pharmacophore features of Hypo 1 and the presence of molecular interactions in co-crystallized FDA-approved drugs. We conclude that the screened hit compounds may act as potent inhibitors of HDAC3 and further preclinical and clinical studies may pave the way for developing them as effective therapeutic agents for the treatment of different cancers and neurodegenerative disorders.

Ameliorative Sexual Behavior and Phosphodiesterase-5 Inhibitory Effects of Spondias mangifera Fruit Extract in Rodents: In Silico, In Vitro, and In Vivo Study

“…Moreover, the RMS fluctuation of PDE5 was also calculated, showing three flexible regions (I, II and III) (Figure 3C). The first flexible region (I) is the short α-helix (672-677) located in the H-loop, which is juxtaposed to the catalytic pocket of the PDE5, with a maximum RMSD deviation of ~0.2 nm [44]. The second flexible region (II) is also located in a loop region (795-800) connecting the α-14 and α-15 helices, with a maximum RMSD ranging from 0.2 to 0.25 nm.…”

Ligands‐induced open‐close conformational change during DapE catalysis: Insights from molecular dynamics simulations

“…Additionally, the absolute values of the binding energies are strongly influenced by the parameters chosen, the charge models, and the simulation length. However, the MMPBSA method offers a reasonable description of the relative binding free energies among different substrates or inhibitors for different Zn 2+ containing proteins 94–96 …”

“…However, the MMPBSA method offers a reasonable description of the relative binding free energies among different substrates or inhibitors for different Zn 2+ containing proteins. [94][95][96]…”

Design, synthesis, and histone deacetylase inhibition study of novel 4‐(2‐aminoethyl) phenol derivatives

“…All the compounds were docked into the HDAC3 active site. [47,48] The AutoDock Vina 1.2.0 (http://vina.scripps.edu) was used throughout the docking protocol. During the docking procedure, the algorithm developed by Vina enables complete flexibility for ligands.…”