In silico molecular docking studies of certain commercially available flavonoids as effective antiviral agents against spike glycoprotein of SARS-CoV-2.

OBJECTIVE: Coronaviruses are large, enveloped, positive-stranded RNA viruses. These viruses contain spike-like projections of glycoprotein on their surface, which appear like a crown. Millions of infections and thousands of deaths have been reported worldwide to date. Hence, the objective of the present study was to look for in silico evaluation of certain commercially available flavonoids against SARS-CoV-2 enzyme. MATERIALS AND METHODS: The in silico docking calculations were carried out using AutoDock 4.2 software. For the computational investigation, Apigenin, Catechin, Galangin, Luteolin, Naringenin were selected. An anti-viral drug Remdesivir was selected as reference drug. RESULTS: In the present study we found that Naringenin showed excellent binding score with the SARS-CoV-2 enzyme compared to the reference drug and other selected flavonoids. CONCLUSIONS: Based on the docking results, we conclude that Naringenin can be considered worthwhile to check its antiviral activity for the management of Coronavirus disease.

Characterization of the Trans-Epithelial Transport of Green Tea (C. sinensis) Catechin Extracts with In Vitro Inhibitory Effect against the SARS-CoV-2 Papain-like Protease Activity.

This work describes an untargeted analytical approach for the screening, identification, and characterization of the trans-epithelial transport of green tea (Camellia sinensis) catechin extracts with in vitro inhibitory effect against the SARS-CoV-2 papain-like protease (PLpro) activity. After specific catechin extraction, a chromatographic separation obtained six fractions were carried out. The fractions were assessed in vitro against the PLpro target. Fraction 5 showed the highest inhibitory activity against the SARS-CoV-2 PLpro (IC50 of 0.125 µg mL-1). The untargeted characterization revealed that (-)-epicatechin-3-gallate (ECG) was the most abundant compound in the fraction and the primary molecule absorbed by differentiated Caco-2 cells. Results indicated that fraction 5 was approximately 10 times more active than ECG (IC50 value equal to 11.62 ± 0.47 µg mL-1) to inhibit the PLpro target. Overall, our findings highlight the synergistic effects of the various components of the crude extract compared to isolated ECG.

Catechins: Therapeutic Perspectives in COVID-19-Associated Acute Kidney Injury.

Data obtained from several intensive care units around the world have provided substantial evidence of the strong association between impairment of the renal function and in-hospital deaths of critically ill COVID-19 patients, especially those with comorbidities and requiring renal replacement therapy (RRT). Acute kidney injury (AKI) is a common renal disorder of various etiologies characterized by a sudden and sustained decrease of renal function. Studies have shown that 5-46% of COVID-19 patients develop AKI during hospital stay, and the mortality of those patients may reach up to 100% depending on various factors, such as organ failures and RRT requirement. Catechins are natural products that have multiple pharmacological activities, including anti-coronavirus and reno-protective activities against kidney injury induced by nephrotoxic agents, obstructive nephropathies and AKI accompanying metabolic and cardiovascular disorders. Therefore, in this review, we discuss the anti-SARS-CoV-2 and reno-protective effects of catechins from a mechanistic perspective. We believe that catechins may serve as promising therapeutics in COVID-19-associated AKI due to their well-recognized anti-SARS-CoV-2, and antioxidant and anti-inflammatory properties that mediate their reno-protective activities.

Theaflavin-3'-O-gallate a Black-tea Constituent Blocked SARS CoV-2 RNA dependant RNA Polymerase Active-site with Better Docking Results than Remdesivir.

BACKGROUND: Replication of SARS-CoV-2 depends on viral RNA-dependent RNA-polymerase (RdRp). Remdesivir, the broad-spectrum RdRp inhibitor acts as nucleoside-analogues (NAs). Remdesivir has initially been repurposed as a promising drug against SARS-CoV-2 infection with some health hazards like liver damage, allergic reaction, low blood-pressure, and breathing-shortness, throat-swelling. In comparison, theaflavin-3'-O-gallate (TFMG), the abundant black tea component has gained importance in controlling viral infection. TFMG is a non-toxic, non-invasive, antioxidant, anticancer and antiviral molecule. RESULTS: Here, we analyzed the inhibitory effect of theaflavin-3'-O-gallate on SARS CoV-2 RdRp in comparison with remdesivir by molecular-docking study. TFMG has been shown more potent in terms of lower Atomic-Contact-Energy (ACE) and higher occupancy of surface area; -393.97 Kcal/mol and 771.90 respectively, favoured with lower desolvation-energy; -9.2: Kcal/mol. TFMG forms more rigid electrostatic and H-bond than remdesivir. TFMG showed strong affinity to RNA primer and template and RNA passage-site of RdRp. CONCLUSIONS: TFMG can block the catalytic residue, NTP entry site, cation binding site, nsp7-nsp12 junction with binding energy of -6. 72 Kcal/mol with Ki value of 11.79, and interface domain with binding energy of -7.72 and -6.16 Kcal/mol with Ki value of 2.21 and 30.71 µM. And most importantly, TFMG shows antioxidant/anti-inflammatory/antiviral effect on human studies.

Severe Acute Respiratory Syndrome Coronavirus-2 Inactivation Activity of the Polyphenol-Rich Tea Leaf Extract with Concentrated Theaflavins and Other Virucidal Catechins.

Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is producing a large number of infections and deaths globally, the development of supportive and auxiliary treatments is attracting increasing attention. Here, we evaluated SARS-CoV-2-inactivation activity of the polyphenol-rich tea leaf extract TY-1 containing concentrated theaflavins and other virucidal catechins. The TY-1 was mixed with SARS-CoV-2 solution, and its virucidal activity was evaluated. To evaluate the inhibition activity of TY-1 in SARS-CoV-2 infection, TY-1 was co-added with SARS-CoV-2 into cell culture media. After 1 h of incubation, the cell culture medium was replaced, and the cells were further incubated in the absence of TY-1. The viral titers were then evaluated. To evaluate the impacts of TY-1 on viral proteins and genome, TY-1-treated SARS-CoV-2 structural proteins and viral RNA were analyzed using western blotting and real-time RT-PCR, respectively. TY-1 showed time- and concentration-dependent virucidal activity. TY-1 inhibited SARS-CoV-2 infection of cells. The results of western blotting and real-time RT-PCR suggested that TY-1 induced structural change in the S2 subunit of the S protein and viral genome destruction, respectively. Our findings provided basic insights in vitro into the possible value of TY-1 as a virucidal agent, which could enhance the current SARS-CoV-2 control measures.

Identifying the natural polyphenol catechin as a multi-targeted agent against SARS-CoV-2 for the plausible therapy of COVID-19: an integrated computational approach.

The global pandemic crisis, coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed the lives of millions of people across the world. Development and testing of anti-SARS-CoV-2 drugs or vaccines have not turned to be realistic within the timeframe needed to combat this pandemic. Here, we report a comprehensive computational approach to identify the multi-targeted drug molecules against the SARS-CoV-2 proteins, whichare crucially involved in the viral-host interaction, replication of the virus inside the host, disease progression and transmission of coronavirus infection. Virtual screening of 75 FDA-approved potential antiviral drugs against the target proteins, spike (S) glycoprotein, human angiotensin-converting enzyme 2 (hACE2), 3-chymotrypsin-like cysteine protease (3CLpro), cathepsin L (CTSL), nucleocapsid protein, RNA-dependent RNA polymerase (RdRp) and non-structural protein 6 (NSP6), resulted in the selection of seven drugs which preferentially bind to the target proteins. Further, the molecular interactions determined by molecular dynamics simulation revealed that among the 75 drug molecules, catechin can effectively bind to 3CLpro, CTSL, RBD of S protein, NSP6 and nucleocapsid protein. It is more conveniently involved in key molecular interactions, showing binding free energy (ΔGbind) in the range of -5.09 kcal/mol (CTSL) to -26.09 kcal/mol (NSP6). At the binding pocket, catechin is majorly stabilized by the hydrophobic interactions, displays ΔEvdW values: -7.59 to -37.39 kcal/mol. Thus, the structural insights of better binding affinity and favorable molecular interaction of catechin toward multiple target proteins signify that catechin can be potentially explored as a multi-targeted agent against COVID-19.

Anti-Influenza with Green Tea Catechins: A Systematic Review and Meta-Analysis.

Influenza is one of the most serious respiratory viral infections worldwide. Although several studies have reported that green tea catechins (GTCs) might prevent influenza virus infection, this remains controversial. We performed a systematic review and meta-analysis of eight studies with 5,048 participants that examined the effect of GTC administration on influenza prevention. In a random-effects meta-analysis of five RCTs, 884 participants treated with GTCs showed statistically significant effects on the prevention of influenza infection compared to the control group (risk ratio (RR) 0.67, 95%CIs 0.51-0.89, P = 0.005) without evidence of heterogeneity (I2= 0%, P = 0.629). Similarly, in three cohort studies with 2,223 participants treated with GTCs, there were also statistically significant effects (RR 0.52, 95%CIs 0.35-0.77, P = 0.001) with very low evidence of heterogeneity (I2 = 3%, P = 0.358). Additionally, the overall effect in the subgroup analysis of gargling and orally ingested items (taking capsules and drinking) showed a pooled RR of 0.62 (95% CIs 0.49-0.77, P = 0.003) without heterogeneity (I2= 0%, P = 0.554). There were no obvious publication biases (Egger's test (P = 0.138) and Begg's test (P = 0.103)). Our analysis suggests that green tea consumption is effective in the prophylaxis of influenza infections. To confirm the findings before implementation, longitudinal clinical trials with specific doses of green tea consumption are warranted.

Significant Inactivation of SARS-CoV-2 In Vitro by a Green Tea Catechin, a Catechin-Derivative, and Black Tea Galloylated Theaflavins.

Potential effects of tea and its constituents on SARS-CoV-2 infection were assessed in vitro. Infectivity of SARS-CoV-2 was decreased to 1/100 to undetectable levels after a treatment with black tea, green tea, roasted green tea, or oolong tea for 1 min. An addition of (-) epigallocatechin gallate (EGCG) significantly inactivated SARS-CoV-2, while the same concentration of theasinensin A (TSA) and galloylated theaflavins including theaflavin 3,3'-di-O-gallate (TFDG) had more remarkable anti-viral activities. EGCG, TSA, and TFDG at 1 mM, 40 µM, and 60 µM, respectively, which are comparable to the concentrations of these compounds in tea beverages, significantly reduced infectivity of the virus, viral RNA replication in cells, and secondary virus production from the cells. EGCG, TSA, and TFDG significantly inhibited interaction between recombinant ACE2 and RBD of S protein. These results suggest potential usefulness of tea in prevention of person-to-person transmission of the novel coronavirus.

EGCG, a Green Tea Catechin, as a Potential Therapeutic Agent for Symptomatic and Asymptomatic SARS-CoV-2 Infection.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged to be the greatest threat to humanity in the modern world and has claimed nearly 2.2 million lives worldwide. The United States alone accounts for more than one fourth of 100 million COVID-19 cases across the globe. Although vaccination against SARS-CoV-2 has begun, its efficacy in preventing a new or repeat COVID-19 infection in immunized individuals is yet to be determined. Calls for repurposing of existing, approved, drugs that target the inflammatory condition in COVID-19 are growing. Our initial gene ontology analysis predicts a similarity between SARS-CoV-2 induced inflammatory and immune dysregulation and the pathophysiology of rheumatoid arthritis. Interestingly, many of the drugs related to rheumatoid arthritis have been found to be lifesaving and contribute to lower COVID-19 morbidity. We also performed in silico investigation of binding of epigallocatechin gallate (EGCG), a well-known catechin, and other catechins on viral proteins and identified papain-like protease protein (PLPro) as a binding partner. Catechins bind to the S1 ubiquitin-binding site of PLPro, which might inhibit its protease function and abrogate SARS-CoV-2 inhibitory function on ubiquitin proteasome system and interferon stimulated gene system. In the realms of addressing inflammation and how to effectively target SARS-CoV-2 mediated respiratory distress syndrome, we review in this article the available knowledge on the strategic placement of EGCG in curbing inflammatory signals and how it may serve as a broad spectrum therapeutic in asymptomatic and symptomatic COVID-19 patients.

Catechin and curcumin interact with S protein of SARS-CoV2 and ACE2 of human cell membrane: insights from computational studies.

The recent outbreak of the coronavirus (SARS-CoV2) is an unprecedented threat to human health and society across the globe. In this context, development of suitable interventions is the need of the hour. The viral spike protein (S Protein) and the cognate host cell receptor ACE2 can be considered as effective and appropriate targets for interventions. It is evident from the present computational study, that catechin and curcumin, not only exhibit strong binding affinity to viral S Protein and host receptor ACE2 but also to their complex (receptor-binding domain (RBD) of the spike protein of SARS-CoV2 and ACE2; RBD/ACE2-complex). The binding affinity values of catechin and curcumin for the S protein, ACE2 and RBD/ACE2-complex are - 10.5 and - 7.9 kcal/mol; - 8.9 and - 7.8 kcal/mol; and - 9.1 and - 7.6 kcal/mol, respectively. Curcumin directly binds to the receptor binding domain (RBD) of viral S Protein. Molecular simulation study over a period of 100 ns further substantiates that such interaction within RBD site of S Protein occurs during 40-100 ns out of 100 ns simulation trajectory. Contrary to this, catechin binds with amino acid residues present near the RBD site of S Protein and causes fluctuation in the amino acid residues of the RBD and its near proximity. Both catechin and curcumin bind the interface of 'RBD/ACE2-complex' and intervene in causing fluctuation of the alpha helices and beta-strands of the protein complex. Protein-protein interaction studies in presence of curcumin or catechin also corroborate the above findings suggesting the efficacy of these two polyphenols in hindering the formation of S Protein-ACE2 complex. In conclusion, this computational study for the first time predicts the possibility of above two polyphenols for therapeutic strategy against SARS-CoV2.

The inhibitory effects of PGG and EGCG against the SARS-CoV-2 3C-like protease.

The coronavirus disease (COVID-19) pandemic, resulting from human-to-human transmission of a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), has led to a global health crisis. Given that the 3 chymotrypsin-like protease (3CLpro) of SARS-CoV-2 plays an indispensable role in viral polyprotein processing, its successful inhibition halts viral replication and thus constrains virus spread. Therefore, developing an effective SARS-CoV-2 3CLpro inhibitor to treat COVID-19 is imperative. A fluorescence resonance energy transfer (FRET)-based method was used to assess the proteolytic activity of SARS-CoV-2 3CLpro using intramolecularly quenched fluorogenic peptide substrates corresponding to the cleavage sequence of SARS-CoV-2 3CLpro. Molecular modeling with GEMDOCK was used to simulate the molecular interactions between drugs and the binding pocket of SARS-CoV-2 3CLpro. This study revealed that the Vmax of SARS-CoV-2 3CLpro was about 2-fold higher than that of SARS-CoV 3CLpro. Interestingly, the proteolytic activity of SARS-CoV-2 3CLpro is slightly more efficient than that of SARS-CoV 3CLpro. Meanwhile, natural compounds PGG and EGCG showed remarkable inhibitory activity against SARS-CoV-2 3CLpro than against SARS-CoV 3CLpro. In molecular docking, PGG and EGCG strongly interacted with the substrate binding pocket of SARS-CoV-2 3CLpro, forming hydrogen bonds with multiple residues, including the catalytic residues C145 and H41. The activities of PGG and EGCG against SARS-CoV-2 3CLpro demonstrate their inhibition of viral protease activity and highlight their therapeutic potentials for treating SARS-CoV-2 infection.

Molecular Descriptors of Some Chemicals that Prevent COVID-19.

BACKGROUND: Topological index is a numerical molecular descriptor that plays an important role in structure-property/structure-activity modeling. A large number of works on multiplicative degree based indices have been developed. However, no attention is paid to investigating their chemical significance. Investigation of the chemical importance of such indices is needed. The computation of topological indices for different chemical structures and networks is a current topic of interest in mathematical chemistry. OBJECTIVE: The objective of the present work is to examine the usefulness of the multiplicative degree based indices in quantitative structure property/activity relationship modeling. In addition, we intend to compute the indices for some anti-COVID-19 chemicals. MATERIALS AND METHODS: The regression analysis for octane data set is performed using MATLAB and Excel to check the predictability of the indices. The sensitivity test is conducted to examine the isomer discrimination ability. To study the indices for chemical structures preventing COVID-19, different combinatorial computation methods are utilized. RESULTS AND DISCUSSION: The regression models governing the structural dependence of different properties and activities are derived. The supremacy of the indices as useful molecular descriptors compared to some well-known and most used descriptors is established. Explicit expressions of the indices for hydroxychloroquine, remdesivir (GS-5734) and theaflavin are obtained. CONCLUSION: As the indices are shown to have remarkable efficiency in quantitative structure property/activity relationship modeling and isomer discrimination, the outcomes can predict different properties and activities of the chemicals under consideration.

A molecular docking study of EGCG and theaflavin digallate with the druggable targets of SARS-CoV-2.

BACKGROUND: COVID-19 is an infectious disease caused by a novel positive-sense single-stranded RNA coronavirus called as SARS-CoV-2. This viral disease is known to infect the respiratory system, eventually leading to pneumonia. Crystallographic studies of the viral structure reveal its mechanism of infection as well as active binding sites and the druggable targets as scope for treatment of COVID-19. HYPOTHESIS: The role of tea polyphenols in prophylaxis and treatment of COVID-19 was established in this study. STUDY DESIGN: Molecular docking interactions of tea polyphenols with some of the possible binding sites of SARS-CoV-2 were performed. MATERIALS AND METHODS: From various studies on the SARS-CoV-2 reported in the literature, we chose possible drug targets (Chymotrypsin-like protease, RNA dependant RNA polymerase, Papain like protease, Spike RBD and ACE2 receptor with spike RBD) which are vital proteins. These receptors were docked against two tea polyphenols, Epigallocatechin gallate (EGCG) from green tea and Theaflavin digallate (TF3) from black tea. These polyphenols have been previously reviewed for their antiviral activities, especially against single-stranded RNA viruses. Two antiviral drugs, Remdesivir and Favipiravir were studied for comparative docking results. RESULTS: A comparative study of docking scores and the type of interactions of EGCG, TF3 with the possible targets of COVID-19 showed that the tea polyphenols had good docking scores with significant in-silico activity. CONCLUSION: These results can provide a lead in exploring both the tea polyphenols in prophylaxis as well as treatment of COVID-19.

Epigallocatechin gallate and theaflavin gallate interaction in SARS-CoV-2 spike-protein central channel with reference to the hydroxychloroquine interaction: Bioinformatics and molecular docking study.

SARS-CoV-2 or COVID-19 pandemic global outbreak created the most unstable situation of human health-economy. In the past two decades different parts of the word experienced smaller or bigger outbreak related to human coronaviruses. The spike glycoproteins of the COVID-19 (similar to SARS-CoV) attach to the angiotensin-converting enzyme (ACE2) and transit over a stabilized open state for the viral internalization to the host cells and propagate with great efficacy. Higher rate of mutability makes this virus unpredictable/less sensitive to the protein/nucleic acid based drugs. In this emergent situation, drug-induced destabilization of spike binding to RBD could be a good strategy. In the current study we demonstrated by bioinformatics (CASTp: computed atlas of surface topography of protein, PyMol: molecular visualization) and molecular docking (PatchDock and Autodock) experiments that tea flavonoids catechin products mainly epigallocatechin gallate or other like theaflavin gallate demonstrated higher atomic contact energy (ACE) value, binding energy, Ki value, ligand efficiency, surface area and more amino acid interactions than hydroxychloroquine (HCQ) during binding in the central channel of the spike protein. Moreover, out of three distinct binding sites (I, II and III) of spike core when HCQ binds only with site III (farthest from the nCoV-RBD of ACE2 contact), epigallocatechin gallate and theaflavin gallate bind all three sites. As sites I and II are in closer contact with open state location and viral-host contact area, these drugs might have significant effects. Taking into account the toxicity/side effects by chloroquine/HCQ, present drugs may be important. Our laboratory is working on tea flavonoids and other phytochemicals in the protection from toxicity, DNA/mitochondrial damage, inflammation and so on. The present data might be helpful for further analysis of flavonoids in this emergent pandemic situation.

The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA polymerase.

An outbreak of coronavirus disease 2019 (COVID-19) occurred in Wuhan and it has rapidly spread to almost all parts of the world. For coronaviruses, RNA-dependent RNA polymerase (RdRp) is an important polymerase that catalyzes the replication of RNA from RNA template and is an attractive therapeutic target. In this study, we screened these chemical structures from traditional Chinese medicinal compounds proven to show antiviral activity in severe acute respiratory syndrome coronavirus (SARS-CoV) and the similar chemical structures through a molecular docking study to target RdRp of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV). We found that theaflavin has a lower idock score in the catalytic pocket of RdRp in SARS-CoV-2 (-9.11 kcal/mol), SARS-CoV (-8.03 kcal/mol), and MERS-CoV (-8.26 kcal/mol) from idock. To confirm the result, we discovered that theaflavin has lower binding energy of -8.8 kcal/mol when it docks in the catalytic pocket of SARS-CoV-2 RdRp by using the Blind Docking server. Regarding contact modes, hydrophobic interactions contribute significantly in binding and additional hydrogen bonds were found between theaflavin and RdRp. Moreover, one π-cation interaction was formed between theaflavin and Arg553 from the Blind Docking server. Our results suggest that theaflavin could be a potential SARS-CoV-2 RdRp inhibitor for further study.