The lack of recommended efficacious drugs or vaccines for the COVID-19 disease caused the ongoing pandemic, which affected 188 countries and territories with 5.20 million confirmed cases and death of 337,000 people by 22 nd May 2020 [1] . The COVID-19 disease caused by the virus strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) identified first in December 2019 at Wuhan, China. SARS-CoV-2, the single-stranded positive-sense RNA virus has beta-coronavirus genus with closely related genomic organization to SARS-CoV identified in 2003 [2] . The envelope of the spherical-shaped SARS-CoV-2 consists of structural proteins like membrane (M), envelope (E) and spike (S) proteins, where the club-shaped spike glycoprotein (SGp) interacts with the angiotensinconverting enzyme 2 (ACE2) of human cells and allows the SARS-CoV-2 virus to enter into the cells [3] . After entering cells, the viral replication and transcription is mediated with functional proteins like main protease (Mpro or 3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp) and helicase [4] . After the publication of the genomic sequence and crystal structures of various proteins of SARS-CoV-2 like Mpro, PLpro, SGp, RdRp etc. [5] [6] [7] [8] , research on structure-based molecular docking, dynamic simulations and quantum mechanical optimizations are performed to discover appropriate inhibitors for SARS-CoV-2 from the available databases/library containing approved drugs and phytochemicals with medicinal importance [9] [10] . The computer based simulations and docking approaches are adopted to expedite the search to get target drugs/molecules from the library/databases that contained in lakhs, and also to minimize the experimental cost and time in developing appropriate drug/vaccine for COVID-19 [11] .
The computational docking and simulations help in repurpose drugs like remdesivir, favipiravir and arbidol to fight against COVID-19 [12] [13] [14] . These repurpose drugs showed some promising results, but required further clinical evidences to examine their safety and efficacy in the treatment of COVID-19 [15] [16] [17] . Therefore, the computational docking and simulations research are ongoing globally to formulate new and effective therapeutic approaches for COVID-19. As a part of our ongoing research to search potential structures from phytochemicals that can effectively bind at the active site of various therapeutic target proteins of SARS-CoV-2 [18] , we selected 186 phenylpropanoids and polyketides based phytochemicals for screening against the proteins 3CLpro, PLpro, SGp, RdRp and ACE2. The phenylpropanoids and polyketides are well known for diverse biological activities and pharmacological properties. Based on the in silico ADMET, druglikeness and dock score, the compounds petunidin, baicalein, cyanidin, hydroxy-3',4'methylenedioxyflavan, quercetin and ellagic acid among the 186 biologically important phenylpropanoids and polyketides were proposed as potential lead compounds, and their interactions with the target proteins were discussed.
The SDF files of the 186 biologically important phenylpropanoids and polyketides were retrieved from EMBL-EBI (www.ebi.ac.uk/chebi/advancedSearchFT.do) and PUBCHEM (https://pubchem.ncbi.nlm.nih.gov/). The structures were re-optimized by semiempirical PM6 method by using the computational code Gaussian 09W and converted to PDB file format [19] . The crystallography protein structure of Mpro (PDB ID: 6LU7), PLpro (PDB ID: 4MM3), RdRp (PDB ID: 6M71), SGp-RDB (PDB ID: 2GHV) and ACE2 (PDB ID: 6M17) were downloaded from the PDB database (www.rcsb.org). The fine structure of the proteins were refined using Swiss model online tools followed by analysed using the Ramachandran plot. The ligand and protein structures were prepared for docking by using the MGL tool. The molecular docking studies were carried out by using the Autodock Vina1.1.2 [20] . The docked structures were analysed using the visualization tool BIOVIA Discovery studio. The important pharmacokinetic properties and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties of the compounds were screened using the online tool SwissADME 'http://www.swissadme.ch/index.php' and 'http://biosig.unimelb.edu.au/pkcsm/prediction'. Table S1 . All the screened compounds showed good dock score, and we found that total 49, 24, 32, 63 and 77 compounds showed more than -8.0 kcal/mol dock score with each of the proteins Mpro, PLpro, SGp, RdRp and ACE2, respectively. To search the potential compounds, we performed protein-ligand interaction study that showed maximum binding affinity and dock score above -8.0 kcal/mol, and filtered the compounds that bound to the active site of any of the therapeutic target proteins of SARS-CoV-2. The protein-ligand interaction study revealed that only 40 compounds are binding at the active site of the therapeutic target proteins of SARS-CoV-2 (Table S2) . These 40 compounds are considered for further screening by in silico ADMET study and drug-likeness prediction.
The ADMET/drug-likeness screening of 40 compounds resulted only 9 compounds (arjunolone, cyanidin, 7-hydroxy-3',4'-methylenedioxyflavan, isorhamnetin, 7,4'dihydroxyflavone, quercetin, baicalein, petunidin and ellagic Acid) which obeying all the limitations of ADMET and drug-likeness properties ( Table S2 ). The predicted drug-likeness properties along with the ADME parameters and pharmacokinetic properties from the SWISSADME and pKcsm online server are summarized in Table S3 . The structure of these lead compounds can be studied for lead optimization to discover novel drugs for COVID-19.
Also, these compounds can be used as an oral and intravenous admissible for further clinical trials. Therefore, a deeper study on the protein-ligand interaction study was performed to examine the modes of interaction of the lead compounds at the active site of the target proteins of SARS-CoV-2.
Based on the dock score and reported medicinal importance of the 9 potential compounds (Table S3) , 6 lead compounds were proposed and their mode of interactions with the residues of target proteins of SARS-CoV-2 at the active site are presented in Table 1 . 
The main protease cleaves about 11 polyproteins including its N and C terminal auto and His41 [21] [22] [23] . Among the screened 9 compounds, the petunidin and baicalein binding at the active site of Mpro with the dock score -8.2 and -8.1 kcal/mol, respectively ( Table 1) . showing hydrogen Bonds to SerA144, Gly143, His163, which indicates the strong binding affinity. Petunidin rings effectively maintaining carbon bond to Cys145 and π-alkyl bond to Met165. The target protein catalytic dyed residues posing π-π bond to His41 and π-donor bond to Phe140 interactions. The closest VDW non-covalent interaction to Asn142, Leu141, His172, Glu166, Leu167, Pro168, Gln189, Arg188, His164, Met49 and Asp187 residues allows to fit ligand in the active pocket (Fig. 1) . The other compound baicalein also showed nearly same binding affinity to Chain A residues by forming hydrogen bonds to Thr6, Thr24, π-cation complex to His41 and unfavourable donor to Cys145 catalytic dyed residues (Fig.   S1 ). Other residues of target protein participate in forming non-covalent interactions are summarized in Table 1 . The petunidin and other anthocyanins synergistically shows carcinogenic effect. In compared to petunidin, the medicinal importance of baicalein is well known [24] . Baicalein shows anti-inflammatory and antitumor effects. It is used in Chinese traditional medicine for treating liver disorders. Also, baicalein acts as an anti-furin activity in CT-26 cells proliferation and migration resulting anti-cancerous properties [25] , which makes baicalein an important inhibitor as the SARS-CoV-2 spike glycoprotein contains a furin cleavage site [26] . Table 1 .
Cyanidin is a pigment found in berries enhancing red, orange and blue colours.
Cyanidin is a polyketide and anthocyanidin pigment found in grapes and red berries.
Cyanidin and its glycoside analogue pose medicinal values such as anti-inflammatory, antidiabetes, anti-obesity and vasoprotective [28] . Anthocyanins structurally similar to cyanidin show anti-cancerous properties and lower the risk of cancer and heart diseases. Cyanidin actively binding to the pocket of catalytic triad residues of PLpro. It is showing binding affinity to PLpro and can be served as an inhibitor. Cyanidin binding to active site of PLpro by forming a complex with Chain B residues showing hydrogen bonds to Gly267, Tyr274
and Asp165 residues. The active site is a hydrophobic cavity showing the ligand forming π-π interactions to Asn268, Tyr265 residues and carbon bond to Pro249 (Fig. 2) . 
SGp plays a vital role in SARS-CoV-2 disease establishment by attaching the cell membrane of the human receptor ACE2 and TMPRSS2 [29, 30] . This also internalizes the virus into the endosomes where the conformational changes take place in the S glycoprotein.
This protein promotes the fusion between the viral protein and the cell membrane constituting kcal/mol (Fig. 3) . It is forming a complex through hydrogen bonds with Arg444, His445 residues, π-π interaction with Phe460 and have non-covalent VDW forces with Asp454, Leu443, Pro477, Arg441, Val456 and Pro459 residues ( Table 1) . Also, 7-hydroxy-3',4'methylenedioxyflavan binding to Chain E amino acid residues forming hydrogen bonds with Pro459, Cys467, π-cation interaction with His445, and π-alkyl bond with Pro466, Val458
( Fig. S2) . The nearest non-covalent VDW interactions with Phe460, Pro477, Leu443, Arg441, Arg444, Ser456, Asp454. Medicinally, 7-hydroxy-3',4'-methylenedioxyflavan is an antiviral drug that is reported for activity against the production of HIV1 antigen in MT4 cells and regression of cell proliferation of MCF7 of BUS cells [31] . Among the 9 lead compounds, computational study revealed quercetin as potent inhibitor of RdRp and binding to polymerase site chain A posing hydrogen bonds to Arg349, Val315, Asn628 and showing π-alkyl, π-cation and π-sigma interactions to Pro677, Arg349, Val315, Pro461, Val675 residues (Fig. 4) . Quercetin forming a strong non-covalent VDW interactions with Phe396, Cys395, Arg457, Thr319, Ser318 ( Table 1 ). In the site2 quercetin binding to the Gln573 and Ser682 residues forming hydrogen bond. The binding of these residues including glycine and serine amino acids of active site cavity with quercetin could hinder the function of RdRp in polymerization. The β strand of nsp12 domain is also encapsulated with quercetin at the active sites 1 and 2.
Quercetin, a flavonoid found in onions, berries and apples etc that is biologically active antioxidant and inflammatory compound. It is an orally admissible drug under investigation that prevents haemolytic, cardiovascular diseases and some of the chronic disorders like diabetes, arthritis, cancer etc. [33] . mainly engages the α1-helix partially from the α2-helix and the linker of the β3 and β4 sheets.
Among the 9 lead compounds, the compounds ellagic acid (Fig. 5) and 7-hydroxy-3',4'-methylenedioxyflavan (Fig. S3) S4) . Another compound hesperidin also a phenolic compounds showing similar binding characteristics to ellagic acid, and binds to Leu95, Gln98, Gln102, Asn194, Asn210, Arg219, Ala396 and Lys562 residues with binding energy -9.2kcal/mol, but this compound violating Lipinski rule for drug-likeness properties.
Therefore, the compounds ellagic acid and 7-hydroxy-3',4'-methylenedioxyflavan were proposed as potent compounds that can inhibit the activity of ACE2. 
In summary, from the in silico computational screening of 186 phenylpropanoids and polyketides based phytochemicals found mainly in Indian medicinal plants and dietary sources, 6 lead compounds (petunidin, baicalein, cyanidin, 7-hydroxy-3',4'methylenedioxyflavan, quercetin and ellagic acid) were proposed as potential against the therapeutic target proteins of SARS-CoV-2. Among the 6 lead compounds, the petunidin and baicalein was proposed to inhibit the function of Mpro. The compounds cyanidin, 7-hydroxy-3',4'-methylenedioxyflavan, quercetin and ellagic acid were proposed for the target proteins PLpro, SGp-RBD, RdRp and ACE2, respectively. These lead compounds are dietary and known for diverse medicinal properties. Therefore, formulation of therapeutic approach for COVID-19 will be easier provided they found experimentally effective in inhibiting the SARS-CoV-2. In addition, it is important to mention here that whenever the phytochemicals are examined, the novel drug delivery systems should be adopted for effective release of the further for lead optimization to discovery novel drug for COVID-19.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.