Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Apr 28;26(9):2584.
doi: 10.3390/molecules26092584.

Binding Free Energy (BFE) Calculations and Quantitative Structure-Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (sm HDAC8) Inhibitors

Conrad V Simoben  1 , Ehab Ghazy  1 , Patrik Zeyen  1 , Salma Darwish  1 , Matthias Schmidt  1 , Christophe Romier  2 , Dina Robaa  1 , Wolfgang Sippl  1
Affiliations

Binding Free Energy (BFE) Calculations and Quantitative Structure-Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (sm HDAC8) Inhibitors

Conrad V Simoben et al. Molecules. .

Abstract

Histone-modifying proteins have been identified as promising targets to treat several diseases including cancer and parasitic ailments. In silico methods have been incorporated within a variety of drug discovery programs to facilitate the identification and development of novel lead compounds. In this study, we explore the binding modes of a series of benzhydroxamates derivatives developed as histone deacetylase inhibitors of Schistosoma mansoni histone deacetylase (smHDAC) using molecular docking and binding free energy (BFE) calculations. The developed docking protocol was able to correctly reproduce the experimentally established binding modes of resolved smHDAC8-inhibitor complexes. However, as has been reported in former studies, the obtained docking scores weakly correlate with the experimentally determined activity of the studied inhibitors. Thus, the obtained docking poses were refined and rescored using the Amber software. From the computed protein-inhibitor BFE, different quantitative structure-activity relationship (QSAR) models could be developed and validated using several cross-validation techniques. Some of the generated QSAR models with good correlation could explain up to ~73% variance in activity within the studied training set molecules. The best performing models were subsequently tested on an external test set of newly designed and synthesized analogs. In vitro testing showed a good correlation between the predicted and experimentally observed IC50 values. Thus, the generated models can be considered as interesting tools for the identification of novel smHDAC8 inhibitors.

Keywords: Schistosoma mansoni; binding free energy calculations; histone deacetylase inhibitors; quantitative structure–activity relationship (QSAR).

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Training set molecules.
Figure 2
Figure 2
(A) 2D plots to visualize the variation of the three most important computed principal components for the training set (Blue box represent the outlier TH58) and (B) 3D visualization of the chemical space occupied by the training set molecules using the first three PCAs.
Figure 3
Figure 3
Re-docked pose in PDB code: 6HRQ. Crystallized ligand and re-docked ligand poses are shown in cyan and magenta, respectively. Protein backbone is shown as a cartoon (white ribbon) and side chains of key amino acid residues in the active sites are shown as white sticks. The catalytic zinc ion and conserved water molecule are shown as orange and red spheres, respectively.
Figure 4
Figure 4
Comparing the docking poses derived from our docking protocol with the crystallized smHDAC8 ligands. Co-crystallized ligands were taken from the corresponding PDB IDs by overlapping (A) PDB ID: 4BZ8, (B) PDB ID: 5FUE, (C) PDB ID: 6HT8 and (D) PDB ID: 6HU1. Co-crystallized ligands with their experimentally determined binding mode are shown in cyan while the docking pose of the ligands from our docking protocol in PDB ID: 6HRQ are shown in magenta. In the different pictures, protein backbones are shown as ribbons and side chains of key amino acid residues in the active sites are shown as white sticks. Catalytic zinc ion and conserved water molecule are shown as orange and red spheres, respectively.
Figure 5
Figure 5
Correlation plot between the experimental pIC50 values (X-axis) and the calculated pIC50 values (Y-axis) for the training set molecules (blue points) using model 95.
Figure 6
Figure 6
Correlation plot between the experimental pIC50 values (X-axis) and the calculated pIC50 values (Y-axis) for the training set molecules (blue points) using model 97 as well as the distribution of the newly designed set of molecules (orange points) along the linear regression line.
Figure 7
Figure 7
Chemical structures of novel smHDAC8 inhibitors used as external test set.
Figure 8
Figure 8
2D plots to visualize the variation of the three most important computed principal components for the test set (Blue box represent the outlier; compound 24).
Figure 9
Figure 9
3D visualization of the first three PCAs to compare the chemical space occupied by training set (green balls) and newly designed molecules (blue balls) while the outlier (compound 24) from the newly designed set is shown as the grey ball.
Figure 10
Figure 10
Structure of the poorly predicted molecule by Model 97.
Figure 11
Figure 11
Comparison of the topped docking pose for the poorly predicted molecule (compound 14; cyan) with a closely related molecule (compound 12; green). Protein backbone is shown as ribbon and side chains of key amino acid residues in the active sites are shown as white sticks. Catalytic zinc ion and conserved water molecule are shown as orange and red spheres, respectively.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. McManus D.P., Dunne D.W., Sacko M., Utzinger J., Vennervald B.J., Zhou X.N. 1236 Schistosomiasis. Nat. Rev. Dis. Primers. 2018;4:13. doi: 10.1038/s41572-018-0013-8. - DOI - PubMed
    1. Barsoum R.S., Esmat G., El-Baz T. Human schistosomiasis: Clinical perspective. J. Adv. Res. 2013;4:433–444. doi: 10.1016/j.jare.2013.01.005. - DOI - PMC - PubMed
    1. World Health Organization Schistosomiasis Facts Sheet. [(accessed on 18 November 2020)];2018 Available online: https://www.who.int/news-room/fact-sheets/detail/schistosomiasis.
    1. King C.H., Sutherland L.J., Bertsch D. Systematic review and meta-analysis of the impact of chemical-based mollusciciding for control of Schistosoma mansoni and S. haematobium transmission. PLoS Negl. Trop. Dis. 2015;9:e0004290. doi: 10.1371/journal.pntd.0004290. - DOI - PMC - PubMed
    1. van der Werf M.J., Bosompem K.M., de Vlas S.J. Schistosomiasis control in Ghana: Case management and means for diagnosis and treatment within the health system. Trans. R. Soc. Trop. Med. Hyg. 2003;97:146–152. doi: 10.1016/S0035-9203(03)90102-7. - DOI - PubMed

MeSH terms

LinkOut - more resources