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The outburst of the COVID-19, with multiple respiratory diseases of varying severity like pneumonia, bronchititis caused by SARS-CoV-2 has created a public health emergency globally. Many existing drugs are under different stages of clinical trials, but no successful drugs have yet been approved to treat COVID-19 diseases. Li & Clercq (2020) proposed several therapeutic options like small molecule drugs, monoclonal antibodies, oligonucleotide-based therapies, peptides, and interferon therapies to prevent or control the pathogen. The typical development time of a drug is 10-15 years (Prakash & Devangi, 2010). In the emergency, a short-term and non-specific solution to combat COVID-19 is repurposing of existing drugs (Fischer et al., 2020; Zhou et al., 2020; Debnath et al., 2020). The fatality ratio of SARS-CoV-1 in the year 2002 in mainland China was the lowest (7%) in comparison to Canada (17%), France (14%), Malaysia (40%), Hong Kong (17%), and they rapidly controlled the outbreak by using herbal formulations from Traditional Chinese Medicine (https://www.who.int/csr/sars/country/table2004_04_21/en/) (Chen et al. 2004; Chen& Nakamura, 2004). About 80% of the world populations rely on traditional medicine which is predominantly based on plant materials (WHO, 1993). Therefore, the other alternative to combat COVID-19 is traditional antiviral herbs (Panyod et al. 2020). Commonly used antiviral drugs often show limited efficacy and serious adverse side effects. Herbal extracts are in use for medicinal purposes since ancient ages and are known for their potential antiviral properties and tolerable side effects. Thus, natural pharmacotherapy may be treated as an alternative to treat viral infections (Ben-Shabat et al. 2020). The available literature on phytochemical analysis showed that alkaloids, phenols, tannins, saponins, anthraquinone, flavonoids, vitamin C, and reducing sugars were found in the leaves of J. adhatoda (Dhankhar et al. 2011; Müller et al. 1993). The pharmacologically most studied bio-active chemical ingredient of the J. adhatoda is a bitter quinazoline alkaloid called vasicin, present in the leaves, roots, and flowers. Besides vasicine, the leaves also contain several alkaloids vasicinone, adhvasinone, vasicinol, anisotine, adhatodine, adhatonine, and hydroxypeganinebetaine, steroids, and alkanes (Mehta et al. 1963). In this pandemic situation, researchers have paid their utmost attention to identify promising inhibitors active against SARS-CoV-2 from natural sources (Sampangi-Ramaiah et al. 2020). Fujimoto et al. 2020 reviewed compounds from 450 herbs having potentiality against SARS-CoV and SARS-CoV-2 crucial life cycle proteins like Mpro, PLpro, RdRp, helicase protein, S protein, N protein, and host enzyme ACE-2. Khaerunnisa et al.2020 reported kaempferol, quercetin, luteolin-7-glucoside, de-methoxy-curcumin, naringenin, apigenin-7-glucoside, oleuropein, curcumin, catechin, and epicatechin-gallate as SARS-CoV-2 Mpro protease inhibitors. It was reported that several plant alkaloids have anti-influenza virus activities (Moradi et al. 2018; Chavan et al. 2014). The methanolic extract of J. adhatoda was the most effective antiviral agent against Herpes Simplex Virus-2 (HSV-2) and even its aqueous extract was found effective against HSV-1 (Joshi et al. 2020). These observations encouraged us to investigate J. adhatoda compounds against SARS-CoV-2 Mpro. In our previous study, we have identified several potential compounds from ten edible spices commonly found in India, and they showed nice binding affinity against two crucial life cycle proteins of SARS-CoV-2 (Sen et al. 2020). Recently, Bag et al. 2020 reported two alkaloids vasicoline and anisotine, from J. adhatoda, which showed a potential binding affinity with Mpro and RdRp of SARS-CoV-2 using molecular docking study. Both the compounds may be used as a drug for respiratory problems. We identified phenolic compounds and one alkaloid showing potential binding affinity against Mpro, which is different from the previous study. In the present study, we have identified SARS-CoV-2 Mpro binding hits from a common variety of shrub, which has been frequently used by people against cough and cold as a part of traditional knowledge (Liu et al. 2019). Not only the binding affinity of the identified hits was impressive, but the selected hits also exhibited interaction with the crucial active site amino acid residues of SARS-CoV-2 Mpro.