Author: MOS Medical Group – Oman
Recent applications of ivermectin to treat Covid-19 by Japanese and Indian has significantly brought down the numbers of both positive cases and hospitalized patients in these two countries. However, the molecular mechanisms of ivermectin that lead to these miracles are not fully understood yet. This article summarizes the recent in silico (computational) studies about the potential mechanisms of ivermectin and shows that this ‘wonder drug’ could target multiple vital proteins throughout the whole infection cycle of SARS-Cov-2.
1. Ivermectin could interfere with the entry of SARS-Cov-2 into human cells
SARS-Cov-2 enters the human cell by first binding to human cell surface receptor protein ACE2 with its spike protein, which is then cut by human serine protease TMPRSS2 [1] and fuse into the cellular membrane. A small molecule that can interrupt this process is a promising drug candidate to treat Covid-19.
Mohammad Reza Dayer reported that among 100 old drugs with high shielding potency towards Spike protein, ivermectin was the best candidate that could bind to the receptor-binding domain (RBD) of the Spike according to the molecular docking results [2]. Later, an independent molecular docking study by Steven Lehrer and Peter Rheinstein showed that ivermectin could bind to the interface between the Spike RBD region and ACE2, which might interfere with the attachment of the Spike to the human cell membrane [3]. Moreover, a molecular dynamic (MD) study by Antonio FranceÅLs-Monerris et al. showed that the binding of ivermectin to the interface between Spike RBD and ACE2 could destabilize their interaction. Their docking results further illustrated that the binding site of ivermectin was different from the natural catalytic site of ACE2, suggesting that ivermectin might be a promising drug as it would not directly perturb the natural catalytic function of ACE2 [4]. In addition to high binding affinity with Spike and ACE2, other in silico studies also showed that ivermectin could efficiently inhibit TMPRSS2 [5, 6].
2. Ivermectin could block the production of proteins for SARS-Cov-2 replication
Once the viral genome is released into the cell, it will hijack the host ribosomes and get translated into a super long polypeptide chain, which is then self-cut by the two proteases, PLpro and Mpro (3CLpro), and end up with 16 non-structural proteins (NSP) which are essential for the SARS-Cov-2 replication. Therefore, a small molecule that can block the activity of the two proteases is a promising drug candidate to treat Covid-19.
Vicky Mody et al. selected 56 drugs from 3897 FDA-approved drugs with the best binding affinity to Mpro, and ivermectin is among the top candidates. The follow-up in vitro study showed that Ivermectin has the lowest IC50 for Mpro among the tested candidates. Their simulation experiment further revealed that the carbonyl group (C=O) in ivermectin could form a hydrogen bond with the catalytic cysteine in Mpro, which explained the ability of ivermectin to interfere with Mpro activity [7]. Other in silico studies also reported that ivermectin is among the best inhibitors for both Mpro and PLpro [5, 6, 8, 9].
3. Ivermectin could interfere SARS-Cov-2 non-structural protein transportation to the nucleus
It was known that ivermectin has broad-spectrum antiviral activity on both RNA and DNA viruses [10]. This property could be attributed to its ability to target the host importin (IMP) α/β1 nuclear transport proteins, which help transport the proteins responsible for replication of the virus to the nucleus [11]. A small molecule that can interrupt this transportation process is a promising drug candidate to treat Covid-19.
Recently, a couple of in silico studies showed that ivermectin is bound to importin with moderate affinity compared with SARS-Cov-2 NSPs [12, 13]. Another molecular dynamic study later demonstrated that ivermectin could remain bound to importin protein [9].
4. Ivermectin might directly inhibit SARS-Cov-2 non-structural protein
SARS-Cov-2 can produce 16 NSPs [14, 15], some of which besides the Mpro and PLpro are also interesting targets to inhibit the replication of SARS-Cov-2.
Malvi Surti et al. reported that among six promising drugs for SARS-Cov-2, ivermectin shows the best inhibitory ability in eight of the nine SARS-Cov-2 target proteins in a molecular dynamics simulation study [8]. Parth Sarthi et al showed that among the 7 NSP understudy, the RNA dependent RNA polymerase (RdRp or nsp12) and the helicase (nsp13) had the strongest affinity to ivermectin [12]. Azam et al. showed that nsp9 had the highest affinity to ivermectin among the NSPs they studied including RdRp and helicase [13]. Molecular dynamic studies also showed that ivermectin can remain bound to 4 of 5 NSPs of SARS-Cov-2 [9].
5. Ivermectin might interfere with the assembly of structural proteins of SARS-Cov-2
In addition to the NSPs, the SARS-Cov-2 genome encodes four structural proteins, including Spike (S), Envelope (E), membrane (M), and nucleocapsid (N) [14, 15]. A small molecule that can target these structural proteins might disrupt the assembly of the SARS-Cov-2. Molecular docking experiments showed that ivermectin had the highest binding affinity with N protein and second-highest binding affinity with M protein among 5 Covid drugs [5].
Conclusion
More and more in vivo studies, in vitro studies, cases studies, and observational studies reported by frontline medical care workers, clinical trials, and epidemiology statistics have shown that ivermectin can greatly reduce the symptoms and hospitalization rate of Covid-19. The recent in silico studies again cross-validated the findings in all the other levels and suggested that the ‘magical’ effect of ivermectin in treating Covid-19 could be attributed to its ability to target multiple viral proteins during the infection cycle of SARS-Cov-2. While multi-target drug design is a trend in the current medicinal chemistry, it seems this 2015 Nobel Prize-winning natural product itself is a multi-target drug designed by nature to treat the Covid-19 pandemic.
References:
[1] Hoffmann, Markus, et al. “SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.” cell 181.2 (2020): 271-280.
[2] Dayer, Mohammad Reza. “Coronavirus (2019-nCoV) deactivation via spike glycoprotein shielding by old drugs, bioinformatics study.” (2020).
[3] Lehrer, Steven, and Peter H. Rheinstein. “Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2.” in vivo 34.5 (2020): 3023-3026.
[4] Francés-Monerris, Antonio, et al. “Microscopic interactions between ivermectin and key human and viral proteins involved in SARS-CoV-2 infection.” Physical Chemistry Chemical Physics 23.40 (2021): 22957-22971.
[5] Eweas, Ahmad F., Amr A. Alhossary, and Ahmed S. Abdel-Moneim. “Molecular docking reveals Ivermectin and Remdesivir as potential repurposed drugs against SARS-CoV-2.” Frontiers in Microbiology 11 (2021): 3602.
[6] Choudhury, Abhigyan, et al. “Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach.” Future Virology 16.4 (2021): 277-291.
[7] Mody, Vicky, et al. “Identification of 3-chymotrypsin like protease (3CLPro) inhibitors as potential anti-SARS-CoV-2 agents.” Communications biology 4.1 (2021): 1-10.
[8] Surti, Malvi, et al. “Ilimaquinone (marine sponge metabolite) as a novel inhibitor of SARS-CoV-2 key target proteins in comparison with suggested COVID-19 drugs: designing, docking and molecular dynamics simulation study.” RSC Advances 10.62 (2020): 37707-37720.
[9] Bello, Martiniano. “Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets.” Journal of Biomolecular Structure and Dynamics (2021): 1-9.
[10] Heidary, Fatemeh, and Reza Gharebaghi. “Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen.” The Journal of antibiotics 73.9 (2020): 593-602.
[11] Wagstaff, Kylie M., et al. “Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus.” Biochemical Journal 443.3 (2012): 851-856.
[12] Sen Gupta, Parth Sarthi, et al. “Binding mechanism and structural insights into the identified protein target of COVID-19 and importin-α with in-vitro effective drug ivermectin.” Journal of Biomolecular Structure and Dynamics (2020): 1-10.
[13] Azam, Faizul, et al. “An in-silico analysis of ivermectin interaction with potential SARS-CoV-2 targets and host nuclear importin α.” Journal of Biomolecular Structure and Dynamics (2020): 1-14.
[14] Zhu, Na, et al. “A novel coronavirus from patients with pneumonia in China, 2019.” New England journal of medicine (2020).
[15] Wu, Fan, et al. “A new coronavirus associated with human respiratory disease in China.” Nature 579.7798 (2020): 265-269.
Edited by: Eglise Bell 圣母院钟声
Proofread by: Eglise Bell 圣母院钟声
Posted by: Eglise Bell 圣母院钟声
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