Binding mechanism and structural insights into the identified protein target of COVID-19 and importin-α with in-vitro effective drug ivermectin

Abstract

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.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• COVID-19
• molecular target
• ivermectin
• antiviral drug
• molecular dynamics

Acknowledgements

P.S.S.G also sincerely acknowledges IISER Berhampur for providing him the Institute Postdoc Fellowship to carry out this work.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

The authors acknowledge IISER Berhampur for computational support.