The novel coronavirus (CoV) is a large family of viruses that causes more severe diseases such as severe acute respiratory syndrome (SARS in 2002-2003) and the middle east respiratory syndrome (MERS in 2012) . In December 2019, unknown pneumonia etiology emerged in Wuhan city, China. They observed symptoms such as dry cough, sore throat, dyspnea, and fever . World Health Organization (WHO) declared that the Public Health Emergency of International Concern of COVID-19 is a pandemic disease by January 2020 . The report states that SARS-CoV-2 is transmitted from bats to humans (i.e., Zoonotic). Later, SARS-CoV-2 transmissions from human to human was confirmed. It causes common cold, lung failure and leads to death . The number of confirmed cases and deaths hikes significantly.
Coronaviruses belong to the subfamily of Coronaviridae and this subfamily includes four genera: i) Alpha coronavirus ii) Beta coronavirus iii) Gamma coronavirus iv) Delta coronavirus. The genome of the CoV is a single-stranded positive-sense RNA virus ((+)ssRNA), it has ~30 kilobase which encodes multiple structural and nonstructural proteins (Nsp1-16) . The structural proteins are Spike (S), Envelope (E), Membrane (M), and Nucleocapsid (N), whereas nonstructural polyproteins (Nsp) are responsible for viral functions, replications and survival in the host cell. Two proteases are 3-chymotrypsin-like-protease (3CLpro) or main protease (Mpro) and Papain-like-protease (PLpro) undergo autocleavage . The report states that human angiotensin-converting enzyme 2 (hACE2)  is the key receptor and main entry point into the cell for SARS-CoV-2 . The spike glycoprotein can bind and then fuse with human cells. Cryo-EM structure analysis has revealed a higher binding affinity for SARS-CoV-2 with human cells of ACE2 than SARS-CoV . It concluded that SARS-CoV-2 has been possessed more transmissibility. Selvam et.al collected a review about targets, structures and inhibitors of SARS-CoV-1, which is helpful to understand the inhibition mechanism of SARS-CoV-2 . Recently, the mutation occurred in genomes of SARS-CoV-2, the most prevalent one is D614G. It is highly contagious than COVID-19 .
PLpro is responsible for the formations of Nsp1-3 and Mpro is responsible for the formations of Nsp4-16. Mpro causes the catalytic cleavage of 11 polyproteins, whereas PLpro causes only 3 polyproteins [13, 14]. Therefore, Mpro is playing a vital role in replications of viral polyproteins and hence it is a potential drug target to inhibit the SARS-CoV-2 [15, 16]. The active site of Mpro has a catalytic dyad, which is formed by His-41 and Cys-145 located in domain I (residues 8-101) and domain II (residues 102-184), respectively. The initial drug addressed in this pandemic is hydroxychloroquine (HCQ), which is an antiviral drug and is used in the treatment of malaria whose action is reinforced with the addition of azithromycin which was reported by the French research society . Also, some of the other antiviral drugs have been used at present in both preventive as well as clinical drugs to treat COVID-19 . Unfortunately, the efficacy and the alarming side-effects of these drugs are still not yet known.
Thus, the design and development of antiviral drug molecules to inhibit the functions of Mpro is essential. Naturally occurring  (i.e., herbal plants and foods) chemical compounds have antiviral activity, used as a medicine worldwide. Herbal plants and their phytoconstituents [20, 21] (extracted from stems, roots, seeds, barks, foods and flowers) result in potential antiviral activity for various diseases and enhance the immune system . In this pandemic COVID-19, the screening of phytoconstituents and their derivatives are helpful into controlling the infections of SARS-CoV-2 . CADD approaches are used to screen and identify the suitable antiviral drugs against Mpro of SARS-CoV-2 . This method is affordable and decreases the time to discover a new antiviral drug candidate. Singam et al. screened the novel inhibitors which are obtained from the Nuclei of Bioassays, Ecophysiology, and Biosynthesis of Natural Products Database (NuBBEDB) against the main protease . Nhung and his co-workers studied the organosulfur compounds from garlic essential oil using gas chromatography-mass spectroscopy (GC-MS) and molecular docking techniques. They found that organosulfur compounds strongly interacted with the human ACE2 and Mpro of SARS-CoV-2 . Kulkarni et al. selected the compounds from various essential oils and their docking analysis reveals that monoterpenes, terpenoid phenols, and phenyl propanoids have a stronger binding affinity with the spike receptor-binding domain (RBD) . Gutierrez-Villagomez et al. studied the antiviral activity of alkamides and piperamides against the Mpro, RdRp (RNA dependent RNA polymerase), and ACE2. They calculated Lipinski’s rule and ADME properties and evaluated the drug-like properties . Recently, Wang et al. reported that the known anticancer drugs act as a potential inhibitor against SARS-CoV-2 Mpro. These results unravel the antiviral activity of naturally occurring compounds and strongly inhibit the replication process of proteases from SARS-CoV-2. Natural products and biocompatible ionic liquids strongly inhibit the Mpro activity.
Even though there are numerous in vivo and in vitro approaches present in the design and development of potential antiviral inhibitors for SARS-CoV-2, still there is a lack of evidence to understand the stability, structural changes and active site interactions of protein-ligand complexes. Our study is mainly focused to find potent antiviral drugs from natural compounds against Mpro and unravel the interaction mechanism of the same. For this, we have selected a series of natural products from various herbal plants (non-toxic with no side effects) and performed docking-based virtual screening, molecular dynamics (MD) simulations and predicted ADME properties. In this work, computational investigations were carried out to evaluate the strong antiviral activity of phytochemicals against Mpro. Molecular-level insights will be helpful to design and develop natural inhibitors to control coronavirus-related disease. Our study will provide potential antiviral drug molecules to strongly inhibit the Mpro of SARS-CoV-2.