Mechanistic insights into the inhibitory activity of FDA approved ivermectin against SARS-CoV-2: old drug with new implications

Abstract

The novel corona virus (Covid-19) has become a great challenge worldwide since 2019, as no drug has been reported yet. Different clinical trials are still under way. Among them is Ivermectin (IVM), an FDA approved drug which was recently reported as a successful candidate to reduce SARS-CoV-2 viral load by inhibiting Importin-α1 (IMP-α1) protein which subsequently affects nuclear transport of viral proteins but its basic binding mode and inhibitory mechanism is unknown. Therefore, we aimed to explore the inhibitory mechanism and binding mode of IVM with IMP-α1 via different computational methods. Initially, comparative docking of IVM was performed against two different binding sites (Nuclear Localization Signal (NLS) major and minor sites) of IMP-α1 to predict the probable binding mode of IVM. Then, classical MD simulation was performed (IVM/NLS-Major site and IVM/NLS-Minor site), to predict its comparative stability dynamics and probable inhibitory mechanism. The stability dynamics and biophysical analysis of both sites highlighted the stable binding of IVM within NLS-Minor site by establishing and maintaining more hydrophobic contacts with crucial residues, required for IMP-α1 inhibition which were not observed in NLS-major site. Altogether, these results recommended the worth of IVM as a possible drug to limit the SARS-CoV-2 viral load and consequently reduces its progression.

Communicated by Ramaswamy H. Sarma

Keywords:

• IVM/IMP-α1 complexes
• MD simulation
• binding-free energy calculation

Acknowledgments

The authors also thank the Deanship of Scientific Research at King Saud University, Saudi Arabia for funding through the research group project no. RGP-1438-043.

Disclosure statement

The authors declare no competing financial interests.

Author contributions

SN and ZU hypothesized and designed the project. SM carried out the benchmarking and docking. UQ set up the MS system and carried out the simulations. SN, SM and UQ drafted the manuscript. ZU, M.N and SA facilitate the research work and reviewed the manuscript. All authors have read and approved the manuscript.