Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical ....

Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical and computational attributes


Introduction

COVID-19 cases are on surge; however, there is no efficient treatment or vaccine that can be used for its management. Numerous clinical trials are being reviewed for use of different drugs, biologics, and vaccines in COVID-19. A much empirical approach will be to repurpose existing drugs for which pharmacokinetic and safety data are available, because this will facilitate the process of drug development. The article discusses the evidence available for the use of Ivermectin, an anti-parasitic drug with antiviral properties, in COVID-19.

Methods

A rational review of the drugs was carried out utilizing their clinically significant attributes. A more thorough understanding was met by virtual embodiment of the drug structure and realizable viral targets using artificial intelligence (AI)-based and molecular dynamics (MD)-simulation-based study.

Conclusion

Certain studies have highlighted the significance of ivermectin in COVID-19; however, it requires evidences from more Randomised Controlled Trials (RCTs) and dose- response studies to support its use. In silico-based analysis of ivermectin’s molecular interaction specificity using AI and classical mechanics simulation-based methods indicates positive interaction of ivermectin with viral protein targets, which is leading for SARS-CoV 2 N-protein NTD (nucleocapsid protein N-terminal domain).

Mechanism of action of ivermectin

Ivermectin enhances the activity of GABA receptors or glutamate-gated chloride ion channels in parasites and helminths which blocks the signal between neuron and muscle. GABA sensitive neurons of mammals are protected by blood brain barrier (BBB), and thus protect vertebrates from possible adverse effects of ivermectin. However, invertebrates are dose-dependently susceptible because of extensive distribution of chloride ion channels, where ivermectin generates Cl− influx, resulting in hyperpolarization which impedes myosin II light chain’s phosphorylation. This promotes paralysis of somatic muscles with concomitant uncoordinated movement, starvation because pharyngeal pumping is inhibited, and death. Ivermectin’s affinity for parasite is 100 times more than for brain of mammals [1]. Immunomodulation of host response is another mechanism by which ivermectin can act achieved by activation of neutrophils, increased C-reactive protein and interleukin-6 levels [8]. For its antiviral activity, ivermectin is believed to act through inhibition of nuclear import of proteins of virus as well as of host. Majority of the RNA virus depend on IMPα/β1 at the time of infection, and ivermectin inhibits this import and enhances the antiviral response [9]. Another mechanism of action by which ivermectin is believed to act involves transmembrane receptor CD147. CD147 along with ACE-2 has been recognized as a key binding site for SARS-CoV-2 spike protein. The potential for major dose–response gains is assessed on the basis of studies that indicate that ivermectin shields SARS-CoV-2 spike protein which binds to CD147 and ACE-2 [6]. Furthermore, Rizzo suggested that ivermectin may have a possible ionophore role. Ionophores have been appreciated for their antibiotic activity and their role as antiviral and anticancer agents is also hypothesized [10].


Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical and computational attributes

Molecular dynamics simulations-based study

Molecular dynamics simulations can be applied to analyze and conclude a framework of molecular level of microbial pathogenesis, but they are still open for improvements in algorithmic precision and methodologies that can effectively assess the bio-system of topics. In this study the molecular interactions of the ivermectin with some primary SARS-CoV-2 protein targets were simulated, namely with nucleocapsid protein N-terminal domain (6M3M), spike S1 RBD (PDB: 6M17), spike S2 fusion domain (6VXX), CL protease (6Y2F), nsp7, nsp8, nsp 12 and nsp13 (6XEZ) as distinct components of RDRP protein and lastly ORF6 protein (I-tasser model) [30,31,32]. The proteins were optimized and simulated at physiological conditions (pH 7.4, Temp = 310 K, Press = 1.01325 Bar). All the simulations were performed on Desmond on Dell Precision tower 3630 with Quadro RTX 4000 GPU computing [33].

The idea that can be obtained from the molecular interaction profile of ivermectin with selected viral proteins is that the ivermectin shows a distinction between the degree of interaction specificity among the various viral targets, but still exhibits comparable binding profile with some. The Cα-RMSD for the 100 ns MD simulation shows the variation in average conformation change influenced by ivermectin on the target proteins (Fig. 2). The extremely smaller protein structures (nsp7, ORF6) encountered higher deviations in overall conformation and opposite implies for the bigger protein (S2 fusion domain). The residue interaction index and trajectory visualization add more to the information about the nature of interaction. It can be deduced that Ivermectin has efficient binding with: (1) spike S1-RBD, where it binds with Thr 500, Asn 501 and Tyr 505 residues (Fig. 3b). These sites are critical to the SARS CoV-2 spike protein-mediated recognition from ACE-2 receptors in the host cellular system. Prominent H-bonding with Thr 500 and Asn 501 and water bridges were observed for more than 80% of simulation (Fig. 4a). (2) Spike S2-fusion domain, it binds to two specific regions of S2 fusion domain namely HR-1 sub-domain and fusion peptide domain. Major interactions were observed at the HR-1 domain, where it binds for up to 80% of simulation duration with Ser 968, Asn 969 and Gly 971 with H-bonds and water bridges. The fusion peptide region also exhibits weak affinity for ivermectin at Phe 797 and extremely weak interactions at Pro 792 residues with hydrophobic contact (Figs. 3c, 4b). The S2 fusion domain is necessary to build the fusion bridge between the viral and host membrane, where the fusion peptide is highly non-polar flexible region which facilitates the direct contact with the host membrane components. (3) N-protein, the poly-nucleotide (RNA) interacting cleft of nucleocapsid N-protein characterized by residues Arg 69, Tyr 124, Asn 127 and Glu 137 were found interacting with ivermectin with rich H-bond ratio, see Figs. 3a and 4c. (4) Main protease, the main protease of the SARS-CoV 2 is another target which exhibits good affinity for ivermectin in inhibition site too at Glu 19, Thr 25, Glu 47, Leu 50 (Figs. 3d, 4d). The spatial localization of ivermectin molecule on the protein surface is illustrated with the active residue characterization in Fig. 5. On the contrary, RDRP components (nsp7, nsp8, nsp12) with helicase (nsp13) and the ORF-6 fragment had weak specificity for ivermectin and could be characterized as weak targets for ivermectin as there was significantly low number of observed drug-protein collisions in simulation.


Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical and computational attributes

Conclusion

Hence, keeping in view the available evidence from clinical studies ivermectin can be a potential drug as it reduced mortality and improved symptoms of patients with COVID-19. Moreover, ivermectin in combination with doxycycline seems effective. However, more RCTs and dose response studies are required to justify its use. The molecular specificity of ivermectin seems to be quite assorted as there can be seen good binding profiles with spike S1 and S2 domains in addition to CL protease inhibition site. The marginally efficient binding to the Nucleocapsid (N) protein might point towards the idea that nucleocapsid activity gets affected after its trans-nuclear import. Hence, ivermectin might be involved in the inhibition of N protein (has a role in nuclear import) and as the exact mechanism is not known, we are describing the best possible target estimation for ivermectin. The findings incline the possibility of ivermectin to be a multi-targeted drug (host and virus-targeted) especially in the case of COVID-19.

Future recommendations

Ivermectin has been reported to show potent efficacy as an antiviral; however, its application is limited because of pharmacokinetic difficulties such as low solubility. These difficulties can be overcome by formulating liposomal ivermectin or other ivermectin formulations with improved properties. Furthermore, inhalation therapy of ivermectin can deliver high drug concentration to the lungs and airways to reduce the viral loads in such areas [41] or else it can be used in combination with other agents that differ in mechanism of action [38].


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