“Recently, ivermectin (a US FDA-approved antiparasitic drug) has been explored as an anti-SARS-CoV-2 agent. Herein, we have studied the possible mechanism of action of ivermectin using in silico approaches. Materials & methods: Interaction of ivermectin against the key proteins involved in SARS-CoV-2 pathogenesis were investigated through molecular docking and molecular dynamic simulation. Results: Ivermectin was found as a blocker of viral replicase, protease and human TMPRSS2, which could be the biophysical basis behind its antiviral efficiency. The antiviral action and ADMET profile of ivermectin was on par with the currently used anticorona drugs such as hydroxychloroquine and remdesivir.
“Ivermectin is a popular choice of drug for treating various parasitic infections till today. Since 1987, this drug has been used to treat more than 3.7 billion onchocerciasis patients through the Mectizan Donation Programme sponsored by Merck for eliminating of onchocerciasis … A major advantage of using this FDA-approved drug is its relatively benign nature at treatment doses in humans . Recently, ivermectin has been reported for antiviral activity toward SARS-CoV-2 in vitro . The study depicts that a low dose of ivermectin (5 micromolar) can induce 93% reduction in viral RNA from released virion and 99.8% reduction in cell-associated/unreleased virion after 24 h of incubation . Researchers have hypothesized that ivermectin binds and impairs Impα/β1 heterodimer, which plays a key role in binding the cargo protein of coronavirus and facilitates its translocation toward the nucleus . Moreover, researchers have also claimed that ivermectin molecules may act as ionophores and be capable of producing osmotic lysis of the viral membrane . Considering the high and rapid viricidal activity of ivermectin, involvement of a specific target is a question. Therefore, the present study was conducted in silico to explore the possible molecular targets of ivermectin in SARS-CoV-2 and the possible mechanism of interactions between ivermectin and the proteins involved in the viral pathogenesis. Such molecular interactions between ivermectin and the target proteins are most likely mediating the rapid and intense antiviral efficacy of ivermectin.
“Spike glycoprotein has been the major viral molecule involved in binding host cell surface receptor and establishing infection . Our molecular docking data and counter verification by molecular dynamic simulation collectively evidenced that ivermectin targets S2 subunit of spike protein and may cause conformational change, which may interfere with spike protein-ACE2 interaction (Figure 1A, Table 1 & Supplementary Table 1). SARS-CoV-2 uses a protease enzyme, namely chymotrypsin-like protease (3CLpro) or main protease (Mpro), which perform an important function to prime spike protein-mediated binding to human ACE2 and entry of the virus . Herein, we checked the interaction between ivermectin and the viral protease and found a strong hydrophobic interaction between these two (Figure 1B & Table 1). Interestingly, the binding efficacy of ivermectin to SARS-CoV-2 replicase/RDRP was to found to be relatively high (Figure 2A–B & Table 1). In fact, ivermectin was found to be the best out of the three drugs in binding with viral replicase (Supplementary Table 2).”