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
. 2022 Apr;40(6):2851-2864.
doi: 10.1080/07391102.2020.1841028. Epub 2020 Nov 2.

An in-silico analysis of ivermectin interaction with potential SARS-CoV-2 targets and host nuclear importin α

Faizul Azam  1 , Ismail M Taban  2   3 , Eltayeb E M Eid  1 , Muzaffar Iqbal  4 , Ozair Alam  5 , Shamshir Khan  6 , Danish Mahmood  7 , Md Jamir Anwar  7 , Habibullah Khalilullah  1 , M U Khan  1
Affiliations

An in-silico analysis of ivermectin interaction with potential SARS-CoV-2 targets and host nuclear importin α

Faizul Azam et al. J Biomol Struct Dyn. 2022 Apr.

Abstract

Ivermectin (IVM) is a broad-spectrum antiparasitic agent, having inhibitory potential against wide range of viral infections. It has also been found to hamper SARS-CoV-2 replication in vitro, and its precise mechanism of action against SARS-CoV-2 is yet to be understood. IVM is known to interact with host importin (IMP)α directly and averts interaction with IMPβ1, leading to the prevention of nuclear localization signal (NLS) recognition. Therefore, the current study seeks to employ molecular docking, molecular mechanics generalized Born surface area (MM-GBSA) analysis and molecular dynamics simulation studies for decrypting the binding mode, key interacting residues as well as mechanistic insights on IVM interaction with 15 potential drug targets associated with COVID-19 as well as IMPα. Among all COVID-19 targets, the non-structural protein 9 (Nsp9) exhibited the strongest affinity to IVM showing -5.30 kcal/mol and -84.85 kcal/mol binding energies estimated by AutoDock Vina and MM-GBSA, respectively. However, moderate affinity was accounted for IMPα amounting -6.9 kcal/mol and -66.04 kcal/mol. Stability of the protein-ligand complexes of Nsp9-IVM and IMPα-IVM was ascertained by 100 ns trajectory of all-atom molecular dynamics simulation. Structural conformation of protein in complex with docked IVM exhibited stable root mean square deviation while root mean square fluctuations were also found to be consistent. In silico exploration of the potential targets and their interaction profile with IVM can assist experimental studies as well as designing of COVID-19 drugs. Communicated by Ramaswamy H. Sarma.

Keywords: Antiviral agents; SARS-CoV-2; docking; ivermectin; molecular dynamics.

PubMed Disclaimer

Conflict of interest statement

No potential conflict of interest was reported by the author.

Figures

Figure 1.
Figure 1.
Chemical structures of the ivermectin used in present study.
Figure 2.
Figure 2.
Docked ivermectin in complex of non-structural protein 9, Nsp9 (A and B), and importin α (C and D). ARM repeats 1-10 of importin α are shown in different colors (C). Broken lines define non-bond interactions in the binding pockets; hydrogen bonds in green whereas hydrophobic interactions in purple color.
Figure 3.
Figure 3.
Most stable conformation of IVM shown as stick rendering in the binding pockets of non-structural protein 9, Nsp9 (A), and importin α (B). Binding pockets are shown as surface rendering and docked ivermectin as stick style.
Figure 4.
Figure 4.
Intermolecular interactions of IVM (shown as stick style) with different COVID-19 proteins after MM/GBSA analysis. A: main protease; B: papain-like protease; C: RdRp (RTP site); D: RdRp (RNA site); E: helicase (Nsp13; ADP site); F: helicase (Nsp13; NCB site); G: Nsp14 (ExoN); H: Nsp14 (N7-methyltransferase).
Figure 5.
Figure 5.
IVM (shown as stick rendering) in complex with several COVID-19 proteins such as spike receptor binding domain (RBD; A), spike monomer (B), spike trimer (C), S2 protein-post fusion state (D), N protein-C domain (E) and N protein-N domain (F) after MM/GBSA computation.
Figure 6.
Figure 6.
The Root Mean Square Deviations (RMSD) of Cα relative to the starting frame during 100 ns MD simulation of IVM in complex with Nsp9 (A) and IMPα (B).
Figure 7.
Figure 7.
Root Mean Square Fluctuations (RMSF) of Nsp9 (A) and importin α (B) residues. The point of contact of ivermectin with protein residues is shown by vertical green lines on X-axis.
Figure 8.
Figure 8.
Nsp9 (A) and importin α (B) interactions with ivermectin, monitored throughout the simulated trajectory of 100 ns. These interactions are clustered by type and summarized in bar diagram including H-bonds, hydrophobic, ionic and water bridges.
Figure 9.
Figure 9.
2D representation of the atomic interactions between ivermectin and Nsp9 residues during 100 ns molecular dynamics simulation.
Figure 10.
Figure 10.
Two-dimensional representation of the atomic interactions between ivermectin and importin α protein residues during 100 ns molecular dynamics simulation.
See this image and copyright information in PMC

References

    1. Ahmed, M. A., Azam, F., Rghigh, A. M., Gbaj, A., & Zetrini, A. E. (2012). Structure-based design, synthesis, molecular docking, and biological activities of 2-(3-benzoylphenyl) propanoic acid derivatives as dual mechanism drugs. Journal of Pharmacy & Bioallied Sciences, 4(1), 43. 10.4103/0975-7406.92728 - DOI - PMC - PubMed
    1. Ahmed, M., Azam, F., Gbaj, A., Zetrini, A. E., Abodlal, A. S., Rghigh, A., Elmahdi, E., Hamza, A., Salama, M., & Bensaber, S. M. (2016). Ester prodrugs of ketoprofen: Synthesis, in vitro stability, in vivo biological evaluation and in silico comparative docking studies against COX-1 and COX-2. Current Drug Discovery Technologies, 13(1), 41–57. - PubMed
    1. Azam, F., Abodabos, H. S., Taban, I. M., Rfieda, A. R., Mahmood, D., Anwar, M. J., Khan, S., Sizochenko, N., Poli, G., Tuccinardi, T., & Ali, H. I. (2019). Rutin as promising drug for the treatment of Parkinson’s disease: An assessment of MAO-B inhibitory potential by docking, molecular dynamics and DFT studies. Molecular Simulation, 45(18), 1563–1571. 10.1080/08927022.2019.1662003 - DOI
    1. Azam, F., Alabdullah, N. H., Ehmedat, H. M., Abulifa, A. R., Taban, I., & Upadhyayula, S. (2018). NSAIDs as potential treatment option for preventing amyloid β toxicity in Alzheimer’s disease: An investigation by docking, molecular dynamics, and DFT studies. Journal of Biomolecular Structure and Dynamics, 36(8), 2099–2117. 10.1080/07391102.2017.1338164 - DOI - PubMed
    1. Azam, F., Amer, A. M., Rabulifa, A., & Elzwawi, M. M. (2014). Ginger components as new leads for the design and development of novel multi-targeted anti-Alzheimer’s drugs: A computational investigation. Drug Design, Development and Therapy, 8, 2045–2059. 10.2147/DDDT.S67778 - DOI - PMC - PubMed