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. 2016 May 6:10:1605-18.
doi: 10.2147/DDDT.S101929. eCollection 2016.

Pharmacoinformatic and molecular docking studies reveal potential novel antidepressants against neurodegenerative disorders by targeting HSPB8

Sheikh Arslan Sehgal  1 , Shazia Mannan  2 , Sannia Ali  2
Affiliations

Pharmacoinformatic and molecular docking studies reveal potential novel antidepressants against neurodegenerative disorders by targeting HSPB8

Sheikh Arslan Sehgal et al. Drug Des Devel Ther. .

Abstract

Charcot-Marie-Tooth (CMT) disease is an inherited peripheral neuromuscular disorder characterized by length-dependent and progressive degeneration of peripheral nerves, leading to muscular weakness. Research has shown that mutated HSPB8 may be responsible for depression, neurodegenerative disorders, and improper functioning of peripheral nerves, resulting in neuromuscular disorders like CMT. In the current work, a hybrid approach of virtual screening and molecular docking studies was followed by homology modeling and pharmacophore identification. Detailed screening analyses were carried out by 2-D similarity search against prescribed antidepressant drugs with physicochemical properties. LigandScout was employed to ascertain novel molecules and pharmacophore properties. In this study, we report three novel compounds that showed maximum binding affinity with HSPB8. Docking analysis elucidated that Met37, Ser57, Ser58, Trp60, Thr63, Thr114, Lys115, Asp116, Gly117, Val152, Val154, Leu186, Asp189, Ser190, Gln191, and Glu192 are critical residues for ligand-receptor interactions. Our analyses suggested paroxetine as a potent compound for targeting HSPB8. Selected compounds have more effective energy scores than the selected drug analogs. Additionally, site-directed mutagenesis could be significant for further analysis of the binding pocket. The novel findings based on an in silico approach may be momentous for potent drug design against depression and CMT.

Keywords: HSPB8; antidepressants; bioinformatics; computer-aided drug design; heat shock protein (HSP); modeling; molecular docking; neurodegenerative disorders; pharmacoinformatics; virtual screening.

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Figures

Figure 1
Figure 1
Root mean square deviation (RMSD) versus time. Notes: HSPB8 showed an increasing trend in RMSD in the first 2 ns. From 2 to 10 nanoseconds, RMSD value continuously increased, while it stabilized for the next 20 nanoseconds.
Figure 2
Figure 2
Root mean square fluctuation (RMSF), showing residue fluctuations. Note: Starting and ending residues showed higher fluctuations during molecular dynamic simulation.
Figure 3
Figure 3
Average root mean square deviation (RMSD) values per frame. Note: Average RMSD seemed to be higher at the start, then fell, depicting stabilization of the structure.
Figure 4
Figure 4
Predicted HSPB8 structure simulated at 30 nanoseconds.
Figure 5
Figure 5
2-D structures of investigated drugs. Notes: (A) Fluoxetine; (B) fluvoxamine; (C) paroxetine; (D) ethacrynic acid.
Figure 6
Figure 6
2-D structures of novel molecules. Notes: (A) PB-765894052; (B) PB-411001374; (C) PB-411001436.
Figure 7
Figure 7
The potential binding interactions of investigated drugs through LigPlot. Notes: (A) Ethacrynic acid; (B) fluoxetine; (C) fluvoxamine; (D) paroxetine.
Figure 8
Figure 8
Binding pocket and interacting residues of novel molecules. Notes: (A) PB-765894052, (B) PB-411001374, (C) PB-411001436.
Figure 9
Figure 9
All the analyzed ligands bound at the same binding pocket in HSPB8.
See this image and copyright information in PMC

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References

    1. Fontaine JM, Rest JS, Welsh MJ, Benndorf R. The sperm outer dense fiber protein is the 10th member of the superfamily of mammalian small stress proteins. Cell Stress Chaperones. 2003;8:62–69. - PMC - PubMed
    1. Kappé G, Franck E, Verschuure P, Boelens WC, Leunissen JA, De Jong WW. The human genome encodes 10 α-crystallin-related small heat shock proteins: HspB1-10. Cell Stress Chaperones. 2003;8:53–61. - PMC - PubMed
    1. Lambert H, Charette SJ, Bernier AF, Guimond A, Landry J. HSP27 multimerization mediated by phosphorylation-sensitive intermolecular interactions at the amino terminus. J Biol Chem. 1999;274:9378–9385. - PubMed
    1. Liu C, Welsh MJ. Identification of a site of Hsp27 binding with Hsp27 and αB-crystallin as indicated by the yeast two-hybrid system. Biochem Biophys Res Commun. 1999;255:256–261. - PubMed
    1. Rogalla T, Ehrnsperger M, Preville X, et al. Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor α by phosphorylation. J Biol Chem. 1999;274:18947–18956. - PubMed

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