Ivermectin tudi po racunalniskih simulacijah (in-silico) ucinkovito deluje proti Sars-Cov2 virusu:
Ivermectin (IVM) is a broad-spectrum antiparasitic agent, having inhibitory potential against wide range of viral infections. It has also been found to hamper SARS-CoV-2 replication in vitro, and its precise mechanism of action against SARS-CoV-2 is ...
www.ncbi.nlm.nih.gov
Conclusion
Ivermectin, a broad-spectrum antiparasitic agent, has been found to inhibit SARS-CoV-2 replication
in vitro. In this study, 15 potential COVID-19 targets were used to underscore IVM affinity by computational techniques employing molecular docking, MM/GBSA computation and molecular dynamics simulation. IMPα protein was also included in this study owing to the reported interaction of IVM with host importin α, resulting in the prevention of nuclear localization signal recognition. Estimation of MM/GBSA based binding energy revealed that Nsp9 possesses highest affinity among COVID-19 targets. Strengths of IVM complex with Nsp9 and IMPα was ascertained by the evaluation of RMSD and RMSF plots obtained after molecular dynamics simulation of 100 ns. Both hydrophobic as well as hydrophilic interactions were identified in anchoring the IVM inside the binding site of Nsp9 as well as major binding groove of the IMPα. Intermolecular interaction profile of IVM disclosed in the current study is expected to assist experimental studies and designing of COVID-19 drugs.
Some clinical studies have indicated activity of ivermectin, a macrocyclic lactone, against COVID-19, but a biological mechanism initially proposed for this anti-viral effect is not applicable at physiological concentrations. This in silico investigation explores potential modes of action of...
www.mdpi.com
Conclusions
In the present study, a computational investigation including molecular docking was conducted to explore the potential bindings of ivermectin and 14 similar compounds to three targets of interest (the spike, CD147 and α7nAChr) that are relevant for drug activity against COVID-19. Strong or moderate affinity bindings were found for ivermectin to multiple sites on the spike protein, CD147 and α7nAChr, which could provide effective competitive bindings to all variants of the virus. According to our calculations, ivermectin binds strongly to a glycosylation binding site (site 10: N61) of the spike protein S1-NTD in the open position and to several other sites on S1 NTD and RBD. We also examined the potential bindings of ivermectin to CD147. Ivermectin was found to bind to site 5, which is located in domain A of the CD147 protein, and to other sites on CD147, indicating that ivermectin might limit glycan bindings of SARS-CoV-2 at the host cell end as well.
Among all the targets, ivermectin has the highest affinity to the α7nAChr receptor. Protein–protein docking results reveal a potential direct binding of the SARS-CoV-2 spike-1 protein to α7nAChr, suggesting that this ubiquitous cholinergic receptor may mediate SARS-CoV-2 entry into cells, shedding light on multiple aspects of SARS-CoV-2 infection pathophysiology (i.e., the loss of smell and taste, the cytokine storm and impairment of the endothelium-dependent acetylcholine-induced vasodilation). In this context, the high affinity of ivermectin and related compounds to α7nAChr may both prevent viral entry and potentiate the activation of the cholinergic pathway and attenuate SARS-CoV-2-induced parasympathetic dysregulation by restoring the function of these receptors. Our preliminary results warrant further in vitro and in vivo testing of the 15 test compounds, in particular ivermectin, an available and safe drug, against SARS-CoV-2, with the hope of containing the virus and limiting its morbidity.
Conclusion
Developing an effective therapeutic against COVID-19 is currently the utmost interest to the scientific communities. The present study depicts comparative binding efficacy of a promising FDA-approved drug, ivermectin, against major pathogenic proteins of SARS-CoV-2 and their human counterparts involved in host–pathogen interaction. Herein, our
in silico data have indicated that ivermectin efficiently utilizes viral spike protein, main protease, replicase and human TMPRSS2 receptors as the most possible targets for executing its antiviral efficiency. Therefore, ivermectin exploits protein targets from both virus and human, which could be the reason behind its excellent
in vitro efficacy against SARS-CoV-2 as reported by Caly
et al. [
13]. Ivermectin B1b isomers have been found to be the more efficacious molecule out of the two homologs. Intriguingly, comparison of the
in silico efficiency of ivermectin with currently used anticorona drugs, such as hydroxychloroquine and remdesivir, indicated toward the potential of ivermectin to target the major pathogenic proteins of SARS-CoV-2. Ivermectin is a popular antiparasitic drug and is also safe in children, younger adults, pregnant and lactating ladies. Development of pulmonary delivery of ivermectin through synthesis of better ivermectin formulation has been reported recently and this is expected to shorten the treatment duration and lead to better outcomes [
33]. It is noteworthy to mention that many anti-SARS-CoV-2s are now being tested for their efficacy in shaping the immune response of humans, through targeting the cell surface as well as intracellular toll-like receptors [
34,
35]. In this context, ivermectin could be an effective option as well. Considering all these facts, the present study explores the therapeutic targets of ivermectin against SARS-CoV-2 and enlightens the possibility of using this drug in COVID-19 clinical trials shortly.
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