Identification of polyphenols fromBroussonetia papyriferaas SARS CoV-2 main protease inhibitors usingin silicodocking and molecular dynamics simulation approaches

Abstract

The current COVID-19 pandemic is caused by SARS CoV-2. To date, $463,000 people died worldwide due to this disease. Several attempts have been taken in search of effective drugs to control the spread of SARS CoV-2 infection. The main protease (Mpro) from SARS CoV-2 plays a vital role in viral replication and thus serves as an important drug target. This Mpro shares a high degree of sequence similarity (>96%) with the same protease from SARS CoV-1 and MERS. It was already reported that Broussonetia papyrifera polyphenols efficiently inhibit the catalytic activity of SARS CoV-1 and MERS Mpro. But whether these polyphenols exhibit any inhibitory effect on SARS CoV-2 Mpro is far from clear. To understand this fact, here we have adopted computational approaches. Polyphenols having proper drug-likeness properties and two repurposed drugs (lopinavir and darunavir; having binding affinity À7.3 to À7.4 kcal/mol) were docked against SARS CoV-2 Mpro to study their binding properties. Only six polyphenols (broussochalcone A, papyriflavonol A, 3'-(3-methylbut-2-enyl)-3',4',7-trihydroxyflavane, broussoflavan A, kazinol F and kazinol J) had interaction with both the catalytic residues (His41 and Cys145) of Mpro and exhibited good binding affinity (À7.6 to À8.2 kcal/mol). Molecular dynamic simulations (100 ns) revealed that all Mpro-polyphenol complexes are more stable, conformationally less fluctuated; slightly less compact and marginally expanded than Mpro-darunavir/lopinavir complex. Even the number of intermolecular H-bond and MM-GBSA analysis suggested that these six polyphenols are more potent Mpro inhibitors than the two repurposed drugs (lopinavir and darunavir) and may serve as promising anti-COVID-19 drugs.

Computer aided identification of potential SARS CoV-2 main protease inhibitors from diterpenoids and biflavonoids of Torreya nucifera leaves

“…One such important anti-HIV drug is lopinavir. In the recent past, lopinavir has been also taken as a standard Mpro inhibitor by us and other investigator (Bhardwaj et al, 2020;Ghosh et al, 2020b). Thus, we have decided to take these two compounds (N3 and lopinavir) as standard inhibitors for this study.…”

“…The overall trends in the several properties after MD simulation remained the same. Finally, we have used the MD trajectories for each system to calculate some important parameters in order to check protein-ligand interactions, namely, root mean square deviation (RMSD), root mean square fluctuation (RMSF), the radius of gyration (Rg), and solvent accessible surface area (SASA) (Ghosh et al, 2020a(Ghosh et al, , 2020b. We also analyzed the secondary structure of Mpro in all these systems as well as analyzed the number of hydrogen bonds formed between Mpro and different compounds (N3, lopinavir, amentoflavone, bilobetin and ginkgetin) throughout the entire MD run (Bharadwaj et al, 2020).…”

“…The sequence of the main protease (Mpro) is highly conserved throughout coronavirus species . The Mpro from SARS CoV-2 is reported to share more than 96% sequence similarity with the same protease from SARS CoV-1 and MERS which makes it an ideal target for broad-spectrum anti-CoV therapy (Ghosh et al, 2020b). Even more sequence similarity is observed between the main protease from SARS CoV-1 and SARS CoV-2 with a difference in only twelve amino acid residues (Supplemental Figure 1; Sequence homology performed using CLUSTALW (1.83) multiple sequence alignment program (Chakraborty et al, 2018;Nandi et al, 2016)) (Macchiagodena et al, 2020).…”

“…Furthermore, various phytochemicals are also proposed as the SARS CoV-2 main protease inhibitors through screening and structure-based design approach (Gorla et al, 2020;Gurung et al, 2020;Mazzini et al, 2020). In recent times, it has been found that plant-derived polyphenols can serve as potent SARS CoV-2 Mpro inhibitors (Bhardwaj et al, 2020;Ghosh et al, 2020aGhosh et al, , 2020bTripathi et al, 2020). Our group has identified three polyphenols from green tea [epigallocatechin gallate (EGCG), epicatechingallate (ECG) and gallocatechin-3-gallate (GCG)] can inhibit the catalytic activity of SARS CoV-2 Mpro (Ghosh et al, 2020a).…”

“…Our group has identified three polyphenols from green tea [epigallocatechin gallate (EGCG), epicatechingallate (ECG) and gallocatechin-3-gallate (GCG)] can inhibit the catalytic activity of SARS CoV-2 Mpro (Ghosh et al, 2020a). In another independent study, we have identified six polyphenols from Broussonetia papyrifera which have the potency to inhibit the proteolytic activity SARS CoV-2 Mpro (Ghosh et al, 2020b). Purohit and coworkers have found that polyphenols such as oolonghomobisflavan-A and theaflavin-3-O-gallate from the tea plant (Camellia sinensis L.) can act as effective SARS CoV-2 Mpro inhibitors (Bhardwaj et al, 2020).…”