The molecular interaction profile of ivermectin

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 a 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 evidence from more Randomised Controlled Trials (RCTs) and dose-response studies to support its use. In a silico-based analysis of ivermectin’s molecular interaction specificity using AI and classical mechanics, simulation-based methods indicate positive interaction of ivermectin with viral protein targets, which is leading for SARS-CoV 2 N-protein NTD (nucleocapsid protein N-terminal domain).

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Mechanism of action of ivermectin

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 a 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 the interaction. It can be deduced that Ivermectin has an 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 the simulation (Fig. 4a). (2) Spike S2-fusion domain, 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 a highly non-polar flexible region that facilitates 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 that 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 the 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 a significantly low number of observed drug-protein collisions in simulation.

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.

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