While an FDA approved drug Ivermectin was reported to dramatically reduce the cell line of SARS-CoV-2 by ∼5000 folds within 48 h, the precise mechanism of action and the COVID-19 molecular target involved in interaction with this in-vitro effective drug are unknown yet.
Among 12 different COVID-19 targets along with Importin-α studied here, the RNA dependent RNA polymerase (RdRp) with RNA and Helicase NCB site show the strongest affinity to Ivermectin amounting −10.4 kcal/mol and −9.6 kcal/mol, respectively, followed by Importin-α with −9.0 kcal/mol. Molecular dynamics of corresponding protein-drug complexes reveals that the drug bound state of RdRp with RNA has better structural stability than the Helicase NCB site and Importin-α, with MM/PBSA free energy of −187.3 kJ/mol, almost twice that of Helicase (−94.6 kJ/mol) and even lower than that of Importin-α (−156.7 kJ/mol). The selectivity of Ivermectin to RdRp is triggered by a cooperative interaction of RNA-RdRp by ternary complex formation. Identification of the target and its interaction profile with Ivermectin can lead to more powerful drug designs for COVID-19 and experimental exploration.
A likely biological mechanism has been indicated to be competitive binding with SARS-CoV-2 spike protein sites, as reviewed [8,9].
[8] Scheim DE. From cold to killer: how SARS-CoV-2 evolved without hemagglutinin esterase to agglutinate, then clot blood cells in pulmo- nary and systemic microvasculature SSRN. 2020. Available from: http:// ssrn.com/abstract=3706347. [Accessed 30 March 2021].
[9] Zaidi AK, Dehgani-Mobaraki P. The mechanisms of action of Iver- mectin against SARS-CoV-2: an evidence-based clinical review article. J Antib 2021. https://doi.org/10.1038/s41429-021-00430-5.
Recently, Dr Satoshi Omura, the Nobel co-laureate for the discovery of IVM, and colleagues conducted a comprehensive review of IVM clinical activity against COVID-19, concluding that the preponderance of the evidence demonstrated major reductions in mortality and morbidity [2]. Our review of that evidence, updated with consideration of several new studies, supports the same conclusion.
Among 12 different COVID-19 targets along with Importin-α studied here, the RNA dependent RNA polymerase (RdRp) with RNA and Helicase NCB site show the strongest affinity to Ivermectin amounting −10.4 kcal/mol and −9.6 kcal/mol, respectively, followed by Importin-α with −9.0 kcal/mol. Molecular dynamics of corresponding protein-drug complexes reveals that the drug bound state of RdRp with RNA has better structural stability than the Helicase NCB site and Importin-α, with MM/PBSA free energy of −187.3 kJ/mol, almost twice that of Helicase (−94.6 kJ/mol) and even lower than that of Importin-α (−156.7 kJ/mol). The selectivity of Ivermectin to RdRp is triggered by a cooperative interaction of RNA-RdRp by ternary complex formation. Identification of the target and its interaction profile with Ivermectin can lead to more powerful drug designs for COVID-19 and experimental exploration.
https://www.tandfonline.com/doi/full/10.1080/07391102.2020.1839564