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
. 2023 May 15;13(1):7870.
doi: 10.1038/s41598-023-33341-6.

Repurposing of drugs against methyltransferase as potential Zika virus therapies

Rohit Shukla #  1   2 , Anshuman Chandra #  3   4 , Anuj Kumar  5   6   7   8 , Pallavi Kandpal  9 , Himanshu Avashthi  10 , Vijay Kumar Goel  4 , Imteyaz Qamar  3 , Nagendra Singh  11 , David J Kelvin  12   13   14 , Tiratha Raj Singh  15   16
Affiliations

Repurposing of drugs against methyltransferase as potential Zika virus therapies

Rohit Shukla et al. Sci Rep. .

Abstract

In recent years, the outbreak of infectious disease caused by Zika Virus (ZIKV) has posed a major threat to global public health, calling for the development of therapeutics to treat ZIKV disease. Several possible druggable targets involved in virus replication have been identified. In search of additional potential inhibitors, we screened 2895 FDA-approved compounds using Non-Structural Protein 5 (NS5) as a target utilizing virtual screening of in-silco methods. The top 28 compounds with the threshold of binding energy -7.2 kcal/mol value were selected and were cross-docked on the three-dimensional structure of NS5 using AutoDock Tools. Of the 2895 compounds screened, five compounds (Ceforanide, Squanavir, Amcinonide, Cefpiramide, and Olmesartan_Medoxomil) ranked highest based on filtering of having the least negative interactions with the NS5 and were selected for Molecular Dynamic Simulations (MDS) studies. Various parameters such as RMSD, RMSF, Rg, SASA, PCA and binding free energy were calculated to validate the binding of compounds to the target, ZIKV-NS5. The binding free energy was found to be -114.53, -182.01, -168.19, -91.16, -122.56, and -150.65 kJ mol-1 for NS5-SFG, NS5-Ceforanide, NS5-Squanavir, NS5-Amcinonide, NS5-Cefpiramide, and NS5-Ol_Me complexes respectively. The binding energy calculations suggested Cefpiramide and Olmesartan_Medoxomil (Ol_Me) as the most stable compounds for binding to NS5, indicating a strong rationale for their use as lead compounds for development of ZIKV inhibitors. As these drugs have been evaluated on pharmacokinetics and pharmacodynamics parameters only, in vitro and in vivo testing and their impact on Zika viral cell culture may suggest their clinical trials on ZIKV patients.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
The brief methodology of the work.
Figure 2
Figure 2
Superimposition of ZIKV methyltransferase with other structures. Inset shows the binding site residues orientation. This figure was generated with the help of UCSF Chimera v.1.13.2 (https://www.cgl.ucsf.edu/chimera/) software.
Figure 3
Figure 3
Binding of drugs to NS5. (A) NS5–SFG, (B) NS5–Ceforanide, (C) NS5–Squanavir, (D) NS5–Amcinonide, (E) NS5–Cefpiramide, and (F) NS5–Olmesartan_Medoxomil. Amino acids interacting with the drugs are represented as negatively charged (orange), positively charged (blue), polar (cyan), and glycine (white), respectively. Binding modes of the drugs were rendered with the help of academic version of Maestro (https://www.schrodinger.com/products/maestro) and PyMOL 2.4 (https://pymol.org/2/) packages.
Figure 4
Figure 4
MDS studies using 150 ns. RMSD and RMSF for drugs binding to NS5. (A) RMSD for all the systems for 150 ns at 300 K. (B) RMSF for all the residues. The apo-NS5 (black) and NS5 complex with SFG (red), Ceforanide (green), Saquinavir (blue), Amcinonide (cyan), Cefpiramide (pink), and Ol_Me (yellow) are represented.
Figure 5
Figure 5
Stability analysis of drugs and NS5 complexes. (A) Rg of all the systems for 150 ns. (B) SASA value for all the systems. (C) Number of hydrogen bonds vs. time for all the ligands including control ligand. The apo-NS5 (black) and NS5 complex with SFG (red), Ceforanide (green), Saquinavir (blue), Amcinonide (cyan), Cefpiramide (pink), and Ol_Me (yellow) are represented.
Figure 6
Figure 6
Principal component analysis. (A) Eigenvalue for the first 50 eigenvectors. (B) 2D projection motions for all the systems. (C) EigenRMSF for all the residues for the PC1. The apo-NS5 (black) and NS5 complex with SFG (red), Ceforanide (green), Saquinavir (blue), Amcinonide (cyan), Cefpiramide (pink), and Ol_Me (yellow) are represented.
Figure 7
Figure 7
Gibbs free energy landscape. (A) apo-NS5, (B) NS5–SFG, (C) NS5–Ceforanide, (D) NS5–Saquinavir, (E) NS5–Amcinonide, (F) NS5–Cefpiramide and (G) NS5–Ol_Me.
Figure 8
Figure 8
Binding free energy decomposition based on residues for all drug–NS5 complexes.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Woolhouse J, Adair ME, Brierley L. RNA viruses: A case study of the biology of emerging infectious diseases. Microbiol. Spectr. 2013;1:1103. doi: 10.1128/microbiolspec.OH-0001-2012. - DOI - PMC - PubMed
    1. Masmejan S, et al. Zika virus. Pathogens. 2020;9:898. doi: 10.3390/pathogens9110898. - DOI - PMC - PubMed
    1. Nandy A, Basak SC. The epidemic that shook the world—The Zika virus rampage. Explor. Res. Hypothesis Med. 2017;2:43–56. doi: 10.14218/ERHM.2017.00018. - DOI
    1. Krauer F, et al. Zika virus infection as a cause of congenital brain abnormalities and Guillain–Barré syndrome: Systematic review. PLoS Med. 2017;14:e1002203. doi: 10.1371/journal.pmed.1002203. - DOI - PMC - PubMed
    1. Plourde AR, Bloch EM. A literature review of Zika virus. Emerg. Infect. Dis. 2016;22:1185. doi: 10.3201/eid2207.151990. - DOI - PMC - PubMed

Publication types

MeSH terms

Grants and funding