Numerous datasets from historic clinical trials are being reviewed in the hope that existing drugs, that have already been cleared for use, might be repurposed to treat patients suffering from severe COVID-19 symptoms.
A recent report explored the evidence available for the use of ivermectin for the treatment of COVID-19. The team reviewed data from clinical trials alongside information about the drug structure and viral targets using an artificial intelligence (AI) and molecular dynamics (MD)-based study.
What is ivermectin?
Ivermectin is an FDA-approved drug with broad antiviral activity, that is currently being used to treat a range of parasitic diseases. It was first discovered in Japan in 1967. In 1987 the drug got approval for the treatment of river blindness, which is caused by Onchocerca volvulus and transmitted by blackfly in humans. It has also historically been used to treat malaria, headlice and scabies. Notably, Ivermectin been reported to exhibit antibacterial and anticancer activities.
Why is ivermectin important for COVID drug development?
Ivermectin is just one of many drugs that has the potential to be repurposed for use against SARS-CoV-2 infection. At the beginning of last year, researchers from the Biomedicine Discovery Institute (BDI) at Monash University in Australia found that ivermectin could stop SARS-CoV-2 growing in a cell culture within two days, with scientists clarifying that even a single dose could essentially remove all viral RNA within 48 hours.
Since then, various clinical studies have been carried out to check the efficacy of ivermectin against SARS-CoV-2 infection, with many reporting optimistic results. A retrospective cohort study of patients with SARS-CoV-2 infection at a hospital in South Florida found that treatment with ivermectin was related to lower mortality, particularly in patients needing ventilator support. Furthermore, numerous studies have reported that the combination of ivermectin and doxycycline is very efficacious in SARS-CoV-2 clearance in patients with mild to moderate disease. In an observational study on COVID-19 patients in Bangladesh, it was found that patients treated with this combination of ivermectin and doxycycline had improved symptoms within 72 hours, no side effects, no required intensive care needs, and no deaths were documented. Correspondingly, according to a prospective comparative study, ivermectin combined with doxycycline was not only safe and efficacious in early viral clearance in patients with mild to moderate COVID disease, but also took less time than the typically preferred hydroxychloroquine and azithromycin combination for viral clearance.
An artificial intelligence and molecular dynamics-based study
Ivermectin and the SARS-CoV-2 protein targets were encoded into a convolutional neural network (CNN) format and the prediction of Drug-Target Interaction (DTI) was made against a trained model available in the BindingDB database, consisting of 13,349 drugs, 1,658 proteins and 74,641 interactions.
Additionally, the molecular interactions of ivermectin with some primary SARS-CoV-2 protein targets were simulated using a Desmond on Dell Precision tower 3630 with Quadro RTX 4000 GPU computing. The molecular interaction profile of ivermectin with selected viral proteins implied that ivermectin shows a distinction between the degree of interaction specificity among the various viral targets, but still exhibits a binding profile with some targets. Notably, the binding coordinates of ivermectin observed were at the prime regions crucial for the activity of particular SARS-CoV-2 proteins. The least structural deviation was observed with the Nucleocapsid protein N terminal domain (NTD), suggesting that ivermectin exhibits relatively high affinity for the Nucleocapsid (N) protein and hence ivermectin may be involved in the inhibition of N protein. These findings insinuate the possibility that ivermectin could be a multi-targeted drug, both host and virus-targeted, particularly in the case of COVID-19.
Analysis of ivermectin’s molecular interaction specificity using AI classical mechanics stimulation-based methods indicates positive interaction of ivermectin with viral protein targets, including the SARS-CoV-2 N-protein NTD. This shows that ivermectin can be thought of as a potential drug for the treatment of COVID-19. This is supported by the beneficial results that have also been observed with ivermectin in clinical studies where the drug reduced mortality and improved symptoms of patients with COVID-19 and its combination with doxycycline seemed effective.
Summary
This study carried out in silico-based analysis of ivermectin’s molecular interaction with SARS-CoV-2 viral proteins to highlight whether the drug could be a potential repurposing candidate for the treatment of severe COVID-19 symptoms. The team used an AI and molecular dynamics-based approach, where SARS-CoV-2 protein targets were encoded into a convolutional neural network format for the prediction of DTIs. Although further clinical trials are needed to support ivermectin’s use as a SARS-CoV-2 therapy, this study highlights an important case study on how AI and molecular dynamics studies can be used to identify existing drugs that can be repurposed to tackle the COVID-19 outbreak.
Image credit: kjpargeter – FreePik
