Abstract: Journal of Biomolecular Structure and Dynamics ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/tbsd20 Mechanistic insights into the inhibitory activity of FDA approved ivermectin against SARS-CoV-2: old drug with new implications Urooj Qureshi, Sonia Mir, Sehrish Naz, Mohammad Nur-e-Alam, Sarfaraz Ahmed & Zaheer Ul-Haq To cite this article: Urooj Qureshi, Sonia Mir, Sehrish Naz, Mohammad Nur-e-Alam, Sarfaraz Ahmed & Zaheer Ul-Haq (2021): Mechanistic insights into the inhibitory activity of FDA approved ivermectin against SARS-CoV-2: old drug with new implications, Journal of Biomolecular Structure and Dynamics, DOI: 10.1080/07391102.2021.1906750 To link to this article: https://doi.org/10.1080/07391102.2021.1906750 Published online: 05 May 2021. Submit your article to this journal Article views: 1701 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=tbsd20 JOURNAL OF BIOMOLECULAR STRUCTURE AND DYNAMICS https://doi.org/10.1080/07391102.2021.1906750 Mechanistic insights into the inhibitory activity of FDA approved ivermectin against SARS-CoV-2: old drug with new implications Urooj Qureshia#, Sonia Mira#, Sehrish Nazb, Mohammad Nur-e-Alamc, Sarfaraz Ahmedc and Zaheer Ul-Haqa,b a H.E.J. Research Institute of Chemistry, ICCBS, University of Karachi, Karachi, Pakistan; bDr. Panjwani Center for Molecular Medicine and Drug Research, ICCBS, University of Karachi, Karachi, Pakistan; cDepartment of Pharmacognosy, King Saud University College of Pharmacy, Riyadh, Kingdom of Saudi Arabia Communicated by Ramaswamy H. Sarma ABSTRACT ARTICLE HISTORY 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-a1 (IMP-a1) 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-a1 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-a1 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 NLSMinor site by establishing and maintaining more hydrophobic contacts with crucial residues, required for IMP-a1 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. Received 21 September 2020 Accepted 17 March 2021