A group of researchers in Biochemistry from several universities in Nigeria have just published a study which demonstrates significant activity of Artemisia annua against the severe acute respiratory syndrome coronavirus (SARS-CoV) and the new SARS-CoV-2.

Identification of Possible Inhibitors of SARS-CoV-2 Main Protease From Some Bioactive Compounds of Artemisia Annua: An in Silico Approach #covid

Introduction

The outbreak of COVID-19, also known as severe acute respiratory syndrome - coronavirus 2 (SARS-CoV-2) has placed the entire world in a stop for some time now. The disease began from Wuhan (Hubei, China) in December 2019, spread to the rest of the world, and has been announced a pandemic by the World Health Organization (WHO). They are the biggest known RNA infections comprising of positive single-stranded RNA and are connected with serious respiratory illness 4,5. SARS-CoV-2 has constrained mankind to be on lockdown as a preventive measure to maintain a strategic distance from disease transmission (contraction and spreading of the illness). The side effects of the sickness incorporate but not restricted to fever, dry hack, sore throat and trouble breathing. As of 3:09pm CEST, 2 May 2021, a total of 151,803,822 established cases of COVID-19 and 3,186,538 deaths have been reported to WHO. Shockingly, there is neither a particular medication endorsed for the treatment of the disease, yet the contamination and death rates are consistently expanding. 

Medications like Lopinavir/Ritonavir and Remdesivir have been under examination and clinical preliminaries towards managing COVID-19. As many countries of the world are continuously relaxing their lockdown limitations, there are worries about the chances of the disease expanding dramatically. Subsequently there is a critical need to distinguish and create novel drugs for the treatment and regulation of SARS-CoV-2 infections. Creating conventional medications and improvement pipelines could however be tedious, expensive and sometimes connected with high clinical disappointments. Nevertheless, medicinal plants have been explored as a rich source of effective bioactive agents against numerous viral infections and several antiviral plant products are suggested to be active against the SARS-CoV-2 Mpro protease.

Artemisia annua is a renowned medicinal plant belonging to the Asteraceae family (Compositae) and it is generally known as sweet wormwood or Qinghao. The identification of the plant and its artemisinin component constituted a major breakthrough in the fight against malaria. Other pharmacological activities have since then been associated with the plant. These include analgesic, anti-inflammatory, antioxidant, immunomodulatory, antibacterial, anticancer and antiviral activities, among others. 

Artemisia annua tea is reported to be effective against several viral infections including herpes simplex virus, dengue virus, human immunodeficiency virus (HIV) and of course, coronavirus. The plant extract showed significant activity against the SARS coronavirus that occurred in 2002 and it was selected for its significant inhibitory effect among 200 Chinese medicinal herbs screened for antiviral activities against SARS-CoV. The plant was also recently reported to possess in vitro inhibitory activity against SARS-CoV-2 replication, but the active compound was not identified. It was however suggested that some non-artemisinin bioactive phytochemicals in the plant extracts could be responsible for the SARS-CoV-2 inhibitory activity, since the observed anti-viral effect did not correlate to the artemisinin component(s) in the extracts. 

Over the years, many bioactive phytochemicals such as terpenoids, tannins, coumarins, essential oils, biflavonoids and polyphenols have been identified from different parts of Artemisia annua and some have been extracted, characterized and analyzed for antiviral activity. Identification of anti-viral compounds of Artemisia annua with SARS-CoV-2 inhibitory activity could therefore help provide a promising therapeutic alternative against COVID-19.

The discovery of novel therapeutics has advanced in the last two decades towards the use of ground-breaking complementary approaches such as computational procedures. In this manner, bioinformatic devices have been used widely in many intriguing investigations; and as of late for the SARS-CoV-2 drug research. Molecular docking, pharmacophore modeling and ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) studies are some of the major computational methods that offer great applicability in a short duration of time. The molecular docking technique assists to predict the binding affinity and inhibitory potential of a test compound (ligand) against a target protein whose modification can produce a therapeutic benefit. A well-recognized molecular target for the development of anti-SARS-CoV-2 drugs is the coronavirus main protease (Mpro), which plays a vital role in viral replication by processing the polyproteins that are translated from the viral RNA. Therefore, the present work carried out detailed in silico analysis, comprising of molecular docking, pharmacophore modeling and ADMET studies of the phytocompounds from Artemisia annua, for the purpose of identifying promising inhibitors of  SARS.

Abstract
Identification of Possible Inhibitors of SARS-CoV-2 Main Protease from some Bioactive Compounds of Artemisia annua: An in silico Approach
The inhibitory potential of Artemisia annua, a well-known antimalarial herb, against several viruses including the coronavirus is increasingly gaining recognition.
The plant extract has shown significant activity against both the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the novel SARS-CoV-2, that is currently ravaging the world. It is therefore necessary to identify the bioactive compounds of the plants that are responsible for this activity, for the purpose of designing drugs against SARS-CoV-2.

In this study, we employed in silico techniques comprising of molecular docking, binding free energy calculations, pharmacophore modelling as well as druglikeness, pharmacokinetics and toxicity predictions, to identify potential inhibitors of the SARS-CoV-2 main protease (Mpro) from 168 bioactive compounds of Artemisia annua.

Rhamnocitrin, Isokaempferide, Kaempferol, Quercimeritrin, Apigenin, Penduletin, Isoquercitrin, Astragalin, Luteolin-7-glucoside and Isorhamnetin were ranked highest; with docking scores ranging from -7.84 to -7.15 kcal/mol compared with -6.59 kcal/mol demonstrated by the standard ligand. Rhamnocitrin, Isokaempferide and Kaempferol, like the standard ligand interacted with important active site amino acid residues like HIS 41, CYS 145, ASN 142, and GLU 166, among others. These compounds also possess acceptable druglike properties and safety profile. Hence, they could be considered for experimental studies and further development into drugs against SARS-CoV-2.

Results
Molecular docking analysis 

The molecular docking analysis showed that the compounds of Artemisia annua possess varying levels of binding affinities for the SARS-CoV-2 main protease, the top ten being Rhamnocitrin (7-Methylkaempferol), Isokaempferide (3-Methylkaempferol), Kaempferol, Quercimeritrin, Apigenin, Penduletin, Isoquercitrin, Astragalin, Luteolin-7-glucoside and Isorhamnetin (figure 1). The binding affinities of these compounds are higher than that of the standard ligand which is -6.59 kcal/mol. Rhamnocitrin scored highest with a docking score of -7.83 kcal/mol followed by Isokaempferide with -7.81 kcal/mol and Kaempferol with -7.65 kcal/mol (table 1). The entire list of the 168 compounds with their docking scores (kcal/mol) and binding free energy (DGbind) MM-GBSA against the SARS-CoV-2 main protease can be found as Supplementary Table S1 online.

Sources:

https://www.researchsquare.com/article/rs-612899/v2

Pdf:
https://assets.researchsquare.com/files/rs-612899/v2/f9a8f561-c7e1-47e9-b3e6-1a3d76575473.pdf