Competitive binding of ribavirin, velpatasvir, and remdesivir to the active site of DNA polymerase can make them repurposable drugs to combat Monkeypox
Shahjahan
, Joy Kumar Dey , Sanjay Kumar Dey
MPV, DNAP, FDA-approved antivirals, ribavirin, velpatasvir, and remdesivir
Inhibition of Monkeypox (MP) viral (MPV) DNA polymerases (DNAP or MP-DNAP) could help the treatment of MPV since these enzymes are essential for its replication. Thus, 90 small molecule antivirals (FDA approved: 75 and investigational: 15) from DrugBank have been virtually screened using two software (i.e., SwissDock and Schrodinger Inc.) against a recently solved cryo-EM structure of MP-DNAP (PDB ID: 8HG1). Current molecular interaction study has revealed that out of the docked 90 antivirals, ribavirin (-9.11/8.92 kcal/mol), velpatasvir (-10.38/-9.66 kcal/mol), and remdesivir (-9.39/-9.23 kcal/mol) can bind to the active site of MP-DNAP, with better efficacies than its substrates (i.e., dCTP (-7.17/-6.83 kcal/mol), dTTP (-7.22/-6.64 kcal/mol), dGTP (-7.48/-7.24 kcal/mol), and dATP (-7.36/-7.09 kcal/mol)). Present study has also unveiled that two WHO approved anti-monkeypox drugs, i.e., cidofovir (-8.46/-8.69 kcal/mol), tecovirimat (-7.7/-7.61 kcal/mol) etc.) could also interact at the substrate binding site of MP-DNAP. These three newly identified antiviral-small molecules as well as cidofovir and tecovirimat could not only interact/bind at the active site residues ASP549, TYR550, ASN551, SER552, LEU553, TYR554, PRO555, ASN665, TYR668, and ASP753 but also, they bind/formed multiple interactions at the active site Mg2+. Therefore, ribavirin, velpatasvir, and remdesivir can plausibly inhibit the substrate/nucleotide binding of MP-DNAP. Since all of these three lead drugs are FDA-approved, they can be directly tested in the MPV infected vero-cells and then undergo clinical trial if cell-based results are promising. Molecular mechanistic studies of complex of all the docked drugs bound to MP-DNAP using Prime-MMGBSA have further confirmed the tight interaction of the best three drugs as revealed by free energy calculations. These three drugs can be repurposed as antivirals against MPV, that may save thousands of human lives, and prevent any future viral epidemics, zoonotic transmissions etc.
"Competitive binding of ribavirin, velpatasvir, and remdesivir to the active site of DNA polymerase can make them repurposable drugs to combat Monkeypox", IJSDR - International Journal of Scientific Development and Research (www.IJSDR.org), ISSN:2455-2631, Vol.8, Issue 10, page no.771 - 784, October-2023, Available :https://ijsdr.org/papers/IJSDR2310119.pdf
Volume 8
Issue 10,
October-2023
Pages : 771 - 784
Paper Reg. ID: IJSDR_209061
Published Paper Id: IJSDR2310119
Downloads: 000347251
Research Area: Other
Country: -, -, India
DOI: https://doi.org/10.5281/zenodo.10676365
ISSN: 2455-2631 | IMPACT FACTOR: 9.15 Calculated By Google Scholar | ESTD YEAR: 2016
An International Scholarly Open Access Journal, Peer-Reviewed, Refereed Journal Impact Factor 9.15 Calculate by Google Scholar and Semantic Scholar | AI-Powered Research Tool, Multidisciplinary, Monthly, Multilanguage Journal Indexing in All Major Database & Metadata, Citation Generator
Publisher: IJSDR(IJ Publication) Janvi Wave
