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Paper Title:	Competitive binding of ribavirin, velpatasvir, and remdesivir to the active site of DNA polymerase can make them repurposable drugs to combat Monkeypox
Authors Name:	Shahjahan , Joy Kumar Dey , Sanjay Kumar Dey
Unique Id:	IJSDR2310119
Published In:	Volume 8 Issue 10, October-2023
Abstract:	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.
Keywords:	MPV, DNAP, FDA-approved antivirals, ribavirin, velpatasvir, and remdesivir
Cite Article:	"Competitive binding of ribavirin, velpatasvir, and remdesivir to the active site of DNA polymerase can make them repurposable drugs to combat Monkeypox", International Journal of Science & Engineering Development Research (www.ijsdr.org), ISSN:2455-2631, Vol.8, Issue 10, page no.771 - 784, October-2023, Available :http://www.ijsdr.org/papers/IJSDR2310119.pdf
Downloads:	000338720
Publication Details:	Published Paper ID: IJSDR2310119 Registration ID:209061 Published In: Volume 8 Issue 10, October-2023 DOI (Digital Object Identifier): https://doi.org/10.5281/zenodo.10676365 Page No: 771 - 784 Publisher: IJSDR \| www.ijsdr.org ISSN Number: 2455-2631

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