Discovery of Potential Plant-derived Iradoides with COVID-19 Mpro in silico

Iradoides are a small class of plant derived natural products, which used in traditional system of medicine such as Unani, Tibetan, Ayurveda, Siddha, and Chinese medicine. The several diverse types of iradoides have been isolated from many parts of the plant such as root, leaves, owers, stem, rhizomes, bark, and seed. Here, we used bioactive iradoides to know the potency against COVID-19 M pro . The COVID-19 M pro is a potential target of the drug, which identied by Chinese scientist (published manuscript in Nature on June 2020). From several studies, we found that many natural products such as avonoids, saponins, steroids, terpenoids, and synthesized compounds have been used on this target (COVID-19 M pro ). We screened a series of iradoides against COVID-19 M pro (PDB ID: 6LU7) by using many docking software as BIOVIA Discovery Studio 2017 R2, Chimera 1.13.1, Auto Dock Tools-1.5.6, AutoDock Vina to known best inhibitor against COVID-19 M pro . According to obtained results, 6′-O-trans-feruloylnegundoside, p-hydroxybenzoyl-6′-O-trans-caffeoylgardoside, 2′-O-p-hydroxybenzoyl gardoside, 6-deoxyharpagide, reptoside show binding energies -8.1, -8.3, -8.2, -7.0, and -7.1 Kcal/mol, respectively. From this study, we found that all iradoides show more potency on COVID-19 M pro when compared with Chloroquine and hydroxychloroquine. The Chloroquine and hydroxychloroquine used as standards for comparison. From the results of this study, we found that iradoides may be useful in the treatment of COVID-19 patients.

Early symptoms of this virus are chest and muscle pain, cough and chills, persistent fever, breathlessness, etc. Severe conditions include sudden confusions, trouble breathing, chest pain, and bluish lips or face [8]. The human infection is spreading from novel SARS-2 β-coronavirus by human to human transmission in the World [9]. Approximately, 15,18,12,556 cumulative cases and 31,86,817 cumulative deaths have been con rmed till 04 may 2021, according to the WHO report [10]. There are not available approved vaccines and drugs for treatment of this infection. Few anti-viral drugs are being used for treatment of this infection, but human infection is being increased day by day [11].
Main protease (M pro ) of SARS-2 is the best target of several drugs. In current, many potential bioactive natural products as saponins, avonoids, steroids, terpenes, are used on COVID-19 M pro in silico [12][13][14]. In this study, we used diverse types of iradoides on this target using molecular docking. The iradoides are a small class of bioactive natural products, which have been reported from several parts of medicinal plants as bark, stem, root, leaves, rhizomes, owers. The several diverse types of iradoides have been used in pharmacology as bacterial infection, malaria, in ammation, neuroprotection, perkinson disease, diabetes, cancer disease etc [15]. The many iradoides glycoside from Fructus gardenia shown antiviral activity against in uenza A virus by PACT-dependent suppression of viral RNA replication [16]. These exhibited an antiasthmatic effect by suppression of elevated IgE, IL-4, and IL-13 level and eosinoplilia in the plasma, so are useful in antiallergic activity [17]. These iradoides increased activities of SOD, NO, GSH,-Px, and NOS production, so are more effective anti-oxidant [18]. The iradoides glycoside restricts HIV-1 replication on the early stage of HIV infection, so shows anti-HIV activity [19]. These increased social interaction time and demonstrated to exert an anxiolytic effect [20]. These iradoides have potent in vitro activity against respiratory syncytial virus [21]. The above activities con rmed that bioactive iradoides are most useful in infection.
The chloroquine is an anti-viral medicine, which have high potential to treat and prevent viral infection [22]. This drug has been used to treat COVID-19 patients, but there is not a speci c treatment for SARS-CoV-2 infection. There is an immediate need of speci c drugs or vaccines to treat of this infection. The computational screening studies can play a pivotal in COVID-19 drug discovery and save money, time resources. In this article, we screened diverse types of plant derived iradoides against COVID-19 Mpro using molecular docking. From these studies, we identi ed the potential of iradoides against COVID-19 M pro .

Preparation of Protein
We obtained protein of COVID-19 M pro from protein data bank (https://www.rcsb.org) (PDB ID: 6LU7) [23]. Protein Data Bank (PDB) is a database of large biological molecules such as nucleic acids and protein. (http://vina.scripps.edu/). In this software, the hydrogen atom and gasteiger charges were added and grid box generated by grid dimension and grid center by proximity to ligand. This protein was saved in a pdbqt format by this software.

Preparation of Ligands
3D-structures of all diverse types of iradoides was performed by using software Chem 3D Pro 12.0.2.1076 (Perkin Elmer, Waltham, US) and saved in PDB format. This PDB le was opened in Auto Dock Tools-1.5.6 software, compute gasteiger charges, non polar hydrogen added. All diverse types ligand (iradoides) was saved in a pdbqt format by this software.

Molecular Docking
The pdbqt le from all diverse types of iradoides and pdbqt le of protein (COVID-19 M pro ) were performed by using Auto Dock Tools-1.5.6 software. The docking calculation of ligand (diverse types of iradoides) with protein was performed on AutoDockVina software (Scripps Research Institute, San Diego, Florida, US). AutoDock Vina is much faster and give more accurate results of ligand-binding a nity. This is free open-source packages and is very easy to use [24]. Vina shows best performance in calculating the ligand-binding a nity for many targets such as amyloid beta 1-40 peptide system [25], cytochrome P450 [26], and in uenza virus [27].
Finally, visualization of all iradoides with protein was performed in BIOVIA Discovery Studio 2017 R2 software (San Diego, CA, USA). Two drugs as chloroquine and hydroxylchloroquine were docked for known binding energy with COVID-19 M pro (in silico). These drugs have high potency and used against COVID-19, experimentally [28]. These effective drugs are utilized as a positive control.
Currently, coronaviruses have a major problem for health, which infecting liver, respiratory, digestive, and central nervous systems humans. There are no speci c clinical treatment SARS-CoV-2 medicated infection [44]. Thus, we urgent, necessary to identify novel drug for treatment of this infection. In the present study, we use medicinal plant derived diverse types of iradoides against COVID-19 M pro in silico. Kcal/mol) with COVID-19 M pro . The Ajuga bracteosa plant has high potential in medicine, which is the main source of these iradoides. These effective iradoides play highly potential role in drug discovery.

Conclusion
In summary, COVID-19 is the major problem of whole world, which being increased day by day. Currently, no speci c drug is available for treatment of this disease. But several drugs are available, which act on M pro for treatment of this disease. Several drugs are being used in trial form for treatment of COVID-19 patients day by day. In the present study, we screened 35 medicinal plants based iradoides with COVID-19 M pro , in which, approximately, 22 iradoides show more binding energy than chloroquine and hydroxychloroquine. From this study, we observed that several diverse types of iradoides target of COVID-19 M pro . So, we need further research on plant based iradoides for treatment of COVID-19.

Con ict of interest
The author declares no con ict of interest.