In a recent study posted to the bioRxiv* preprint server, researchers repurposed medications for the monkeypox virus in silico.
Study: In silico repurposed drugs against monkeypox virus. Image Credit: FOTOGRIN/Shutterstock
This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
Background
Monkeypox is caused by the monkeypox virus belonging to the Orthopoxviruses clade, which encompasses cowpox, smallpox, variola, and vaccinia. The monkeypox virus is endemic to Central and West Africa.
The incidence of monkeypox is rising globally with a 2022 outbreak that has expanded to Europe during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The unique, priorly unidentified viral mutations and variants are linked to the recent outbreak of monkeypox.
Tecovirimat is currently the only poxvirus medication approved by the United States (US) Food and Drug Administration (FDA). Otherwise, there is a small pharmacopeia and little interest in monkeypox research.
About the study
In the current research, the investigators used molecular dynamics (MD) and virtual screening to examine the possible repurposing of several drugs that had already received FDA or similar regulatory agency approval for other diseases for treating monkeypox infections.
The team investigated five poxvirus targets: A50R, A48R, D13L protein trimer complex, I7L, and F13L. They all have been recommended as beneficial intervention targets by earlier reviews and studies. Following the derivation of these targets, the researchers used numerous sequence alignments to determine the active protein residues in monkeypox. As a result, they proposed eight brand-new, probably repurposable monkeypox drugs.
Moreover, poxvirus sequences were procured from the nucleotide database of the National Center for Biotechnology Information (NCBI) in Singapore to align numerous sequences with other poxviruses. During MD and virtual screening, the D13L and A48R structures were modeled utilizing priorly experimentally derived configurations, namely protein Data Bank (PDB) 6BED and 2V54, respectively.
Results
According to the study results, the eight drugs possibly repurposed for monkeypox were nilotinib for A50R, rutaecarpine, and NMCT for A48R, naldemedine and hypericin for F13L, simeprevir for D13L, and lixivaptan and fosdagrocorat for I7L.
The study results showed that various premature stop codons, polymorphisms, and duplications were found across the French isolate for all proteins assessed. Despite the broken frames, the locations of these polymorphisms were generally conserved and not on any relevant active residues.
In MD simulations using the CHARMM36m force field, every drug examined demonstrated high stability. Hydrophobic interactions further validated this inference, highlighting the significant potential of analyzed drugs as a monkeypox treatment option. Furthermore, the study data depicted that the number of hydrophobic interactions may influence the stability of a drug.
The stability and clustering pose validated the structural active and binding domains for proteins obtained from AlphaFold2. Tecovirimat and mitoxantrone docked steadily and robustly to the pockets close to the active regions throughout the simulation. This observation supports earlier research that demonstrated the effectiveness of these medications in blocking poxviruses and provides in silico proof for the position of the pocket. TTP-6171 also exhibited notably strong adhesion to the I7L region, bolstering its ability as a potential monkeypox treatment by further establishing its capacity to halt viral replication.
Tyr-144 was discovered as a novel amino acid of interest for the protein A48R. Gln-27 for D13L also illustrated hydrogen bonding to rifampin and simeprevir, suggesting its potential significance for further research. The other residues identified as crucial for F13L were Asn-329, Ser-135, Asn-312, and Asp-331.
Due to the emergence of antiviral resistance, the previously known medication rifampin, which binds to D13L, has not been utilized to treat poxvirus infections. Additionally, the robust Gly-27 bond that D13L forms with both rifampin and simeprevir suggest a potential hotspot for antiviral resistance since a mutation of this compound could mean the loss of a constant strong hydrogen bond.
Previous vaccinia mutations also illustrated resistance to tecovirimat and mitoxantrone in different locations. Although the active residues were discovered using these regions, these mutations might also induce other medications ineffective. A drug cocktail could be employed to circumvent this, such as one that is recommended in contexts with significant antimicrobial resistance, to eradicate the virus without allowing it the chance to mutate due to evolutionary pressure.
Conclusions
The study findings predicted that multiple drugs adhere strongly to monkeypox proteins, essential for viral replication. These medications include molecules expressing a strong affinity for the monkeypox D13L capsid protein, whose suppression impedes viral replication.
The researchers noted the adoption of the possible targets nilotinib for A50R, rutaecarpine and NMCT for A48R, naldemedine and hypericin for F13L, simeprevir for D13L, and lixivaptan and fosdagrocorat for I7L and controls mentioned in the paper should be probed further to lower the deaths associated with the viruses. In addition, they anticipate that the current epidemics and pandemics, such as monkeypox and coronavirus disease 2019 (COVID-19), would attract much-needed attention to illnesses presently being ignored and encourage much-warranted study.
This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources
Article Revisions
- May 15 2023 - The preprint preliminary research paper that this article was based upon was accepted for publication in a peer-reviewed Scientific Journal. This article was edited accordingly to include a link to the final peer-reviewed paper, now shown in the sources section.
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