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1.
Phys Chem Chem Phys ; 23(27): 14873-14888, 2021 Jul 14.
Article in English | MEDLINE | ID: covidwho-1541260

ABSTRACT

The COVID-19 disease caused by the virus SARS-CoV-2, first detected in December 2019, is still emerging through virus mutations. Although almost under control in some countries due to effective vaccines that are mitigating the worldwide pandemic, the urgency to develop additional vaccines and therapeutic treatments is imperative. In this work, the natural polyphenols corilagin and 1,3,6-tri-O-galloy-ß-d-glucose (TGG) are investigated to determine the structural basis of inhibitor interactions as potential candidates to inhibit SARS-CoV-2 viral entry into target cells. First, the therapeutic potential of the ligands are assessed on the ACE2/wild-type RBD. We first use molecular docking followed by molecular dynamics, to take into account the conformational flexibility that plays a significant role in ligand binding and that cannot be captured using only docking, and then analyze more precisely the affinity of these ligands using MMPBSA binding free energy. We show that both ligands bind to the ACE2/wild-type RBD interface with good affinities which might prevent the ACE2/RBD association. Second, we confirm the potency of these ligands to block the ACE2/RBD association using a combination of surface plasmon resonance and biochemical inhibition assays. These experiments confirm that TGG and, to a lesser extent, corilagin, inhibit the binding of RBD to ACE2. Both experiments and simulations show that the ligands interact preferentially with RBD, while weak binding is observed with ACE2, hence, avoiding potential physiological side-effects induced by the inhibition of ACE2. In addition to the wild-type RBD, we also study numerically three RBD mutations (E484K, N501Y and E484K/N501Y) found in the main SARS-CoV-2 variants of concerns. We find that corilagin could be as effective for RBD/E484K but less effective for the RBD/N501Y and RBD/E484K-N501Y mutants, while TGG strongly binds at relevant locations to all three mutants, demonstrating the significant interest of these molecules as potential inhibitors for variants of SARS-CoV-2.


Subject(s)
Antiviral Agents/chemistry , Gallic Acid/analogs & derivatives , Glucose/analogs & derivatives , Glucosides/chemistry , Hydrolyzable Tannins/chemistry , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Binding Sites , Gallic Acid/chemistry , Glucose/chemistry , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Mutation , Protein Binding/drug effects , Protein Interaction Domains and Motifs/genetics , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
2.
Drug Res (Stuttg) ; 71(8): 462-472, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1404894

ABSTRACT

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.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , Biflavonoids/pharmacology , COVID-19/drug therapy , Catechin/pharmacology , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Gallic Acid/analogs & derivatives , Molecular Docking Simulation , SARS-CoV-2/drug effects , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/pharmacology , Alanine/chemistry , Alanine/pharmacology , Antiviral Agents/chemistry , Biflavonoids/chemistry , COVID-19/virology , Catalytic Domain , Catechin/chemistry , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Enzyme Inhibitors/chemistry , Gallic Acid/chemistry , Gallic Acid/pharmacology , Protein Conformation , SARS-CoV-2/enzymology , Structure-Activity Relationship
3.
Molecules ; 26(12)2021 Jun 11.
Article in English | MEDLINE | ID: covidwho-1270089

ABSTRACT

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.


Subject(s)
Antiviral Agents/pharmacology , Biflavonoids/chemistry , Catechin/chemistry , Gallic Acid/analogs & derivatives , SARS-CoV-2/physiology , Tea/chemistry , Virus Replication/drug effects , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antiviral Agents/chemistry , Biflavonoids/pharmacology , COVID-19/pathology , COVID-19/virology , Catechin/analogs & derivatives , Catechin/pharmacology , Cell Survival/drug effects , Chlorocebus aethiops , Gallic Acid/chemistry , Gallic Acid/pharmacology , Humans , Protein Interaction Maps/drug effects , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Tea/metabolism , Vero Cells
4.
Comput Biol Med ; 129: 104137, 2021 02.
Article in English | MEDLINE | ID: covidwho-938857

ABSTRACT

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.


Subject(s)
Antiviral Agents/chemistry , Biflavonoids/chemistry , Catechin/analogs & derivatives , Gallic Acid/analogs & derivatives , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , Biflavonoids/pharmacology , Binding Sites , Catechin/chemistry , Catechin/pharmacology , Gallic Acid/chemistry , Gallic Acid/pharmacology , Molecular Docking Simulation
5.
Drug Dev Res ; 82(1): 86-96, 2021 02.
Article in English | MEDLINE | ID: covidwho-696175

ABSTRACT

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.


Subject(s)
Biflavonoids/metabolism , Catechin/analogs & derivatives , Computational Biology/methods , Gallic Acid/analogs & derivatives , Hydroxychloroquine/metabolism , Molecular Docking Simulation/methods , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Biflavonoids/chemistry , Binding Sites/physiology , COVID-19/metabolism , Catechin/chemistry , Catechin/metabolism , Gallic Acid/chemistry , Gallic Acid/metabolism , Humans , Hydroxychloroquine/chemistry , Protein Structure, Secondary , Protein Structure, Tertiary , Spike Glycoprotein, Coronavirus/chemistry , X-Ray Diffraction/methods
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