A Bioinformatics Study of Structural Perturbation of 3CL-Protease and the HR2-Domain of SARS-CoV-2 Induced by Synergistic Interaction with Ivermectins

The pandemic caused by SARS-CoV-2 forces drug research to combat it Ivermectin, an FDA approved antiparasitic drug formulated as a mixture 80:20 of the equipotent homologous 22,23 dihydro ivermectin (B1_a and B1_b), which is known to inhibit SARS-CoV-2 in vitro with a mechanism of action to be defined It draws attention powerfully that the energetic and structural perturbation that this drug induces by binding on SARS-COV-2 proteins of importance for its proliferation is ill unknown Hence what we do an exhaustive computational biophysics study to discriminate the best docking of ivermectins to viral proteins and, subsequently, to analyze possible structural alterations with molecular dynamics The results suggested that ivermectins are capable of docking to the superficial and internal pocket of the 3CL-protease and the HR2-domain, inducing unfolding/folding that change the native conformation in these proteins In particular, ivermectin binds to the 3CL protease and leads this protein to an unfolded state, whereas the HR2-domain to a more compact conformation in comparison to the native state by refolding when the drug binding to this protein The results obtained suggest a possible synergistic inhibitory against SARS-COV-2 owing to each role of ivermectins when favorably binding to these viral proteins Given the importance of the results obtained about this new mechanism of action of ivermectin on SARS-CoV-2, experimental studies are needed that corroborate this proposal