Binding affinities analysis of ivermectin, nucleocapsid and ORF6 proteins of SARS-CoV-2 to human importins α isoforms: A computational approach

Ivermectin has been shown in vitro that reduces SARS-CoV-2 replication in infected cells through interactions with importins α, however, the exact mechanism of action is still unknown. The objective of this study was to analyze binding affinities of ivermectin, SARS-CoV-2 nucleocapsid (N) and ORF6 proteins, to isoforms of human importins α using molecular docking methods. Crystallized structures of importins α from Protein Data Bank (PDB) and AlphaFold Protein Structure Database were used, viral proteins were modeled using AlphaFold 2. Molecular docking simulations were performed between human importin α isoforms, ivermectin, N and ORF6 proteins, employing Broyden-Fletcher-Goldfarb-Shanno, FTDock and pyDockRST algorithms. Data obtained evidenced that viral proteins of SARS-CoV-2 and ivermectin showed favorable binding affinities to ARM2-ARM4 domains (major binding site), sharing binding affinities to the same active residues. These results suggest that ivermectin shares the same active site on the α-importins as the SARS-CoV-2 N and ORF6 proteins, demonstrating a potential molecular target for research in the development of new antiviral drugs against COVID-19.