The word “corona” means crown. The series of crown-like spikes on the surface of the virus endorses the name Coronavirus which is known to cause flu-like symptoms including fever, cough, malaise, dyspnea, fatigue, sore throat, and pneumonia1,2 The highly pathogenic human coronavirus (HCoVs) is, SARS-CoV, MERS-CoV, and SARS-CoV-2. CoVs exhibit similarities in the genome, morphological structures, and functions of Structural (SPs), Nonstructural (NSPs), and accessory proteins.3 The SPs such as spike, envelop, membrane and nucleocapsid proteins, protease, and Nonstructural Proteins (NSPs) derived from Polyproteins (PP1a, PP1ab) are a few well-validated targets to design and develop antiviral agents.4

The majority of the clinical signs and symptoms of CoV infections share a commonality but they differ in mortality rate, with COVID-19 being less compared to others. All these infections primarily target the lungs, but in severe form, the infection may spread to other vital organs such as the heart, liver, Gastrointestinal Tract (GIT), and kidneys.5

The multi-organ manifestations of the three forms of the coronaviruses are displayed in Table 1. Both SARS-CoV and SARS-CoV-2 cause respiratory syndrome by binding strongly with Angiotensin-Converting Enzyme 2 (ACE2), present in the host organs. While interacting with the host targets, the spike-glycoprotein of these viruses plays a critical role. The Mpro enzyme (main protease) contributes to the cleavage of polyproteins, and hence significant for viral replication. In the absence of specific treatment, antiviral agents (remdesivir, molnupiravir), antibiotics (azithromycin, macrolide antibiotics, paxlovid) and corticosteroids were extensively used to control the COVID-19 infection worldwide.6–8

Sl. No. Description/Manifestation SARS-CoV MERS-CoV COVID-19 1 Source Bats Camels Bats 2 Type β-CoVs β-CoVs β-CoVs 3 Functional receptors ACE 2 — ACE 2 4 Treatment Antibiotics, Ribavirin and corticosteroids, Chemokine immunotherapy. Antibiotics, Corticosteroids, Ribavirin and IV Immunoglobulin (IVIG). Glucocorticoids, IL-6 antagonists, Janus Kinase Inhibitors, Chloroquine. 5 Pulmonary Manifestation Cough, Hypoxia, Acute Respiratory Distress Syndrome (ARDS). Dyspnea, Cough and ARDS. Sore throat, Abnormal chest computed tomography, Thromboembolism, Cytokine-mediated injury of lungs. 6 CVS Manifestations Tachycardia, Hypotension, Acute onset myocarditis. Severe chest pain, Heart Failure, Increased levels of pro-brain, anti-natriuretic peptide levels (Pro BNP). Hypertension, Increased levels of high-sensitivity cardiac troponin-I, Overexpression of ACE2. 7 Hepatobiliary Manifestations Increased levels of ALT and AST, Hyperglycemia. Increased Dipeptidyl Peptidase-4(DPP4). Increased levels of liver enzymes, Bilurubin and LDH.Patients with fatty liver have a high incidence of disease. 8 GIT Loss of appetite, Diarrhea, Nausea, Vomiting and abdominal pain. Abdominal pain and Fever. Loss of appetite, Diarrhea, Nausea, Vomiting and abdominal pain, Patients with BMI-35kg/m2 are more susceptible to infection. 9 Renal Manifestation No acute renal damage Renal damage. Acute renal edema and inflammation. 10 Neurological Manifestation Ischemic Stroke, Seizures, Neuropathy and myopathy. Both central and peripheral neurological disorders. Sudden onset of anosmia and dysgeusia. 11 Musculo cutaneous Myalgia Muscle atrophy Myalgia, Muscle aches. 12 Haematological Manifestation Reactive Lymphocytosis and Severe lymphopenia. Lymphopenia Lymphopenia. Table 1:
Multi-organ Manifestations of SARS-CoV, MERS-CoV, and COVID-19.

Natural products are affective to treat several infections and fatal diseases caused by bacteria, virus and other parasites. Chalcones are precursors for flavonoids, isoflavonoids, and aurones. The majority of the bioactive chalcones are rich in phenolic functionality and exhibit significant antioxidant potential.9 Chalcones display antiviral activity by blocking the activities of crucial antiviral target enzymes such as topoisomerase-II, protein kinases, and proteases. Few chalcones were identified as protease inhibitors when tested against different types of coronaviruses.10 Duran et al. isolated several alkylated chalcones from plant sources and reported their inhibitory potential against SARS-CoV protease.11 A variety of flavonoids and chalcones were found to interact and bind effectively with therapeutically important SARS-CoV2 proteins like Mpro, RNA dependent-RNA polymerase, and spike protein.12,13

Alkaloids related to protoberberine, aporphine, benzylisoquinoline, morphinan, and benzophenanthirine classes are associated with potent antiviral activity. After the COVID-19 outbreak, various alkaloids were studied using in silico approaches to predict binding affinity towards COVID-19 targets.14–16 Berberine, tetrandrine, and morphine were also tested in clinical trials related to complications associated with COVID-19.17,18

COVID-19 is now a global health issue and studies to investigate promising therapies are urgently needed.

Molecular docking and dynamic studies are often employed in an attempt to discover chemical agents that could strongly bind at the target binding site. Hence, to find the best natural compounds that firmly bind and establish better interactions with COVID-19 receptors, molecular docking, and then molecular dynamic studies were performed on a set of twenty natural compounds (Table 2).

Sl. No. Compound Name Classification 1. Tetrandrine Bis-benzylisoquinoline alkaloid 2. Colchicine Tropane alkaloid 3. Quinine Alkaloid 4. Lycorine Pyrrolo[de]phenanthridine ring-type alkaloid 5. Tylophorine Phenanthraindolizidine alkaloid 6. Herbacetin Flavonol 7. Isoliquiritigenin Chalcone 8. Butein Chalcone 9. Cardamonin Chalcone 10. Cinanserine Cinnamide derivative 11. Acetyl-L- carnitine Amino acid derivative 12. Carnosine It is a dipeptide made up of β-alanine and histidine 13. N-acetylcysteine (NAC) Amino acid derivative 14 Etoposide Podophyllotoxin derivative 15 Cannabidiol (CBD) Phytocannabinoid 16. Xanthonrhizol Sesquiterpenoid 17. Curcumin Diaryl heptanoid (curcuminoids) 18. Liquorice Triterpene glycoside 19. Silvestrol Cyclopenta [b]benzofuran flavagline 20. Remdesivir Remdesivir is a phosphoramidite prodrug. Table 2:
Natural compounds selected for the molecular docking study with Mpro.