LitCovid-sentences  

PMC:7441777 / 2037-51517 JSONTXT 12 Projects

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Id Subject Object Predicate Lexical cue
T23 0-2 Sentence denotes 1.
T24 4-16 Sentence denotes Introduction
T25 17-112 Sentence denotes An outbreak of Coronavirus disease (COVID-19) has caused a pandemic situation across the globe.
T26 113-310 Sentence denotes Although the outburst was first observed at Wuhan city in China, at present more than 200 countries and territories around the world have witnessed the COVID-19 fatalities affecting all age groups.
T27 311-462 Sentence denotes As of July 03, 2020, more than 11 million people have been affected by the disease, with a fatality of 5,25,410 across the globe as per the WHO report.
T28 463-549 Sentence denotes Unfortunately, there is no clinically approved drug or vaccine for COVID-19 as of now.
T29 550-928 Sentence denotes The disease is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), a member of the Coronaviridae family of viruses and it belongs to the same family Betacoronaviruses, like Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) (Chan et al., 2015; Elfiky & Azzam, 2020; Ibrahim et al., 2020).
T30 929-1059 Sentence denotes The symptoms of SARS-CoV-2 infection include fever, dry cough, shortness of breath, runny nose, and sore throat (Wu et al., 2020).
T31 1060-1271 Sentence denotes SARS-CoV-2 is a positive-sense single-stranded RNA virus, and its genome is around 29.7 kB long with twelve putative open reading frames (ORFs) that encode different viral structural and non-structural proteins.
T32 1272-1530 Sentence denotes There are four structural proteins in SARS-CoV-2, namely spike (S), envelope (E), membrane (M), and nucleocapsid (N), and all of them can potentially serve as an antigen for neutralizing antibody preparation as potential therapeutics (Boopathi et al., 2020).
T33 1531-1751 Sentence denotes Another potential drug target for SARS-CoV-2 is RNA‐dependent RNA polymerase (RdRp) (Figure 1), which is a key component of the replication machinery of the virus to make multiple copies of the RNA genome (Elfiky 2020c).
T34 1752-1805 Sentence denotes RdRp in various coronaviruses are remarkably similar.
T35 1806-1898 Sentence denotes For example, the RdRp of SARS-CoV exhibits ∼97% sequence similarity with that of SARS-CoV-2.
T36 1899-2236 Sentence denotes More importantly, there is no human polymerase counterpart that resembles the sequence/structural homology with RdRp from coronaviruses, and hence, the development of RdRp inhibitors could be a potential therapeutic strategy without risk of crosstalk with human polymerases (Borgio et al., 2020; Subissi et al., 2014; Zhai et al., 2005).
T37 2237-2617 Sentence denotes Very recently, Yin et al. reported the crystal structure RdRp of SARS-CoV-2 complexed with an antiviral drug, Remdesivir highlighting how the template-primer RNA is recognized by the polymerase enzyme and the chain elongation is inhibited by Remdesivir providing a basis for developing a wide range of effective inhibitors to overcome from SARS-CoV-2 infection (Yin et al., 2020).
T38 2618-2811 Sentence denotes RdRp has been found to be an effective drug target for several other RNA viruses, spanning from the hepatitis C virus, zika virus to coronaviruses (Elfiky, 2017, 2019; Ganesan & Barakat, 2017).
T39 2812-2976 Sentence denotes The active site of RdRp is highly conserved, and the catalytic domains contain two consecutive aspartate residues in a beta-turn joining β15 and β16 (Elfiky 2020c).
T40 2977-3212 Sentence denotes The general structure of RdRp consists of 7 motifs (A to G) among them inner channel of catalytic sites represented by motif A to C, and they play a crucial role during the nucleotide addition cycle (Jia & Gong, 2019; Wu & Gong, 2018).
T41 3213-3222 Sentence denotes Figure 1.
T42 3224-3299 Sentence denotes The 3-dimensional crystal structure of RNA‐dependent RNA polymerase (RdRp).
T43 3300-3663 Sentence denotes Epidemiological studies repetitively suggested that consumption of bioactive compounds (e.g. vitamins, phytochemicals, polyphenols, flavonoids, flavonols, and carotenoids etc.) has beneficial activity on human health and could minimize the risk of various diseases starting from cancers to different viral infections (Khan et al., 2020; Szajdek & Borowska, 2008).
T44 3664-3846 Sentence denotes Traditional natural compounds have been consumed since ancient times as they exhibit less toxicity, low-cost availability, minimum side-effects and are rich in therapeutic resources.
T45 3847-4132 Sentence denotes Some of the previous findings also suggest that naturally occurring compounds possess a wide range of antiviral properties against RNA viruses, including polio-virus type 1, parainfluenza virus type 3, and respiratory syncytial virus by inhibiting their replication (Lin et al., 2014).
T46 4133-4429 Sentence denotes In that context, Ahmed-Belkacem et al. have screened more than forty potent natural flavonoids for their polymerase inhibition activity using HCV-NS5 strain and among the different flavonoids, quercetagetin showed strong HCV replication inhibitory activity in vitro (Ahmed-Belkacem et al., 2014).
T47 4430-4604 Sentence denotes Previously, song et al. reported that green tea catechins, by disrupting the membrane of the influenza virus, inhibited neuraminidase in the crude system (Song et al., 2005).
T48 4605-4759 Sentence denotes On a separate report, Takashi et al. reported that EGCG, a green tea polyphenol can inhibit the endonuclease activity of influenza A virus RNA polymerase.
T49 4760-4905 Sentence denotes EGCG is also reported to interfere with viral replication via modulating the cellular redox environment (Ho et al., 2009; Kuzuhara et al., 2009).
T50 4906-5112 Sentence denotes Therefore, the existing scientific evidence strongly suggests that natural flavonoids/polyphenol can act against SARS-CoV-2 (Aanouz et al., 2020; Elfiky 2020b; Elmezayen et al., 2020; Enmozhi et al., 2020).
T51 5113-5454 Sentence denotes Because of the time-consuming process of new synthetic/semi-synthetic drug development, drug repurposing of phytomolecules is an ideal alternative in this urgent situation as the latter process is economical and scalable in a very short period of time (Adeoye et al., 2020; Islam et al., 2020; Muralidharan et al., 2020; Sinha et al., 2020).
T52 5455-5617 Sentence denotes Hence, a comprehensive understanding of their binding to SARS-CoV-2 RdRp can yield interesting findings that can further be capitalized to develop COVID-19 drugs.
T53 5618-5770 Sentence denotes Nevertheless, the apparent lack of cytotoxicity of polyphenols at even significantly high concentrations makes them potential antiviral drug candidates.
T54 5771-5898 Sentence denotes In the present study, we selected a hundred natural polyphenols to assess their potential to act as SARS-CoV-2 RdRp inhibitors.
T55 5899-6069 Sentence denotes The selected library was then explored to evaluate the binding affinity of individual polyphenols towards RdRp of the SARS-CoV-2 by molecular docking using AutoDock vina.
T56 6070-6388 Sentence denotes Among the selected polyphenols, theaflavin (TF1), theaflavin-3′-O-gallate (TF2a), theaflavin-3′-gallate (TF2b), theaflavin 3,3′-digallate (TF3), hesperidin, EGCG, myricetin, and quercetagetin were found to be docked in the active site of RdRp of the SARS-CoV-2 with a highly favourable affinity for the binding pocket.
T57 6389-6550 Sentence denotes Further to get a better understanding of the dynamics of the complexes, we performed a 150-nanoseconds molecular dynamic simulation with those eight polyphenols.
T58 6551-6617 Sentence denotes The binding free energy components were calculated by the MM-PBSA.
T59 6618-6738 Sentence denotes Remdesivir (Hendaus, 2020) and GTP (a physiological nucleotide) were taken as positive controls to validate our results.
T60 6740-6742 Sentence denotes 2.
T61 6744-6765 Sentence denotes Materials and methods
T62 6767-6771 Sentence denotes 2.1.
T63 6773-6798 Sentence denotes Molecular docking studies
T64 6800-6806 Sentence denotes 2.1.1.
T65 6808-6828 Sentence denotes Protein preparations
T66 6829-6878 Sentence denotes The crystal structure of SARS-CoV-2 RdRp (PDB ID:
T67 6879-6981 Sentence denotes 6M71) (Yan et al., 2020) was retrieved from the protein databank (www.rcsb.org) (Berman et al., 2000).
T68 6982-7144 Sentence denotes The crystal structure was prepared individually by adding hydrogen atoms and computing the Gasteiger charge using the AutoDock v4.2 program (Morris et al., 2009).
T69 7145-7232 Sentence denotes Subsequently, the file was saved as .pdbqt format in preparation for molecular docking.
T70 7233-7376 Sentence denotes Schematic representation of the work-flow for selecting potential natural polyphenolic inhibitors for the SARS-CoV-2 RdRp is shown in Figure 2.
T71 7377-7386 Sentence denotes Figure 2.
T72 7388-7498 Sentence denotes Flow chart of the methodology for shortlisting the best natural polyphenolic inhibitor of the SARS-CoV-2 RdRp.
T73 7500-7506 Sentence denotes 2.1.2.
T74 7508-7527 Sentence denotes Ligand preparations
T75 7528-7740 Sentence denotes The SDF structures of GTP, remdesivir, and selected hundred polyphenols (see Table S1 in Supplementary Information) were retrieved from the PubChem database (https://pubchem.ncbi.nlm.nih.gov/) (Kim et al., 2019).
T76 7741-7898 Sentence denotes The compounds were converted into PDB format, and conformational energies of all the compounds were minimized by using UCSF Chimera (Pettersen et al., 2004).
T77 7899-7907 Sentence denotes Table 1.
T78 7909-8055 Sentence denotes Binding energy (kcal/mol) of the natural polyphenols along with the control compounds (GTP and remdesivir) against RdRp of the SARS-CoV-2 (PDB ID:
T79 8056-8089 Sentence denotes 6M71) by molecular docking study.
T80 8090-8092 Sentence denotes S.
T81 8093-8096 Sentence denotes No.
T82 8098-8142 Sentence denotes Compound Name Binding energy (kcal/mol) S.
T83 8143-8146 Sentence denotes No.
T84 8148-8188 Sentence denotes Compound Name Binding energy (kcal/mol)
T85 8189-8223 Sentence denotes 1 TF3 −9.9 52 Cyanidin −6.3
T86 8224-8259 Sentence denotes 2 TF2b −9.6 53 Daidzein −6.3
T87 8260-8295 Sentence denotes 3 TF1 −9.6 54 Glycitein −6.3
T88 8296-8330 Sentence denotes 4 TF2a −9.3 55 Wogonin −6.3
T89 8331-8373 Sentence denotes 5 Hesperidin −8.8 56 Phloretin −6.3
T90 8374-8409 Sentence denotes 6 EGCG −7.3 57 Catechin −6.2
T91 8410-8453 Sentence denotes 7 Myricetin −7.2 58 Urolithin B −6.2
T92 8454-8500 Sentence denotes 8 Quercetagetin −7.0 59 Angolensin −6.2
T93 8501-8541 Sentence denotes 9 Quercetin −6.9 60 Pinosylvin −6.2
T94 8542-8584 Sentence denotes 10 Curcumin −6.9 61 Formononetin −6.2
T95 8585-8637 Sentence denotes 11 Dihydrorobinetin −6.8 62 Liquiritigenin −6.2
T96 8638-8676 Sentence denotes 12 Peonidin −6.8 63 Prunetin −6.2
T97 8677-8715 Sentence denotes 13 Fisetin −6.8 64 Alpinetin −6.2
T98 8716-8758 Sentence denotes 14 Robinetin −6.7 65 Biochanin A −6.2
T99 8759-8809 Sentence denotes 15 5-Deoxygalangin −6.7 66 Rhapontigenin −6.1
T100 8810-8851 Sentence denotes 16 Kaempferol −6.7 67 Genistein −6.1
T101 8852-8893 Sentence denotes 17 Scutellarein −6.7 68 Chrysin −6.1
T102 8894-8947 Sentence denotes 18 (-)-Epicatechin −6.7 69 6-Hydroxyflavone −6.1
T103 8948-8983 Sentence denotes 19 Purpurin −6.7 70 Equol −6.1
T104 8984-9029 Sentence denotes 20 Isorhamnetin −6.7 71 Piceatannol −6.1
T105 9030-9076 Sentence denotes 21 Tricetin −6.6 72 Isorhapontigenin −6.0
T106 9077-9120 Sentence denotes 22 Gossypetin −6.6 73 Resveratrol −5.8
T107 9121-9163 Sentence denotes 23 Norathyriol −6.6 74 Danshensu −5.7
T108 9164-9203 Sentence denotes 24 Coumestrol −6.6 75 Eugenin −5.6
T109 9204-9252 Sentence denotes 25 Isosakuranetin −6.6 76 Sinapic acid −5.5
T110 9253-9304 Sentence denotes 26 Pectolinarigenin −6.6 77 Pterostilbene −5.5
T111 9305-9349 Sentence denotes 27 Tangeritin −6.6 78 Ferulic acid −5.4
T112 9350-9393 Sentence denotes 28 Nobiletin −6.6 79 Caffeic acid −5.4
T113 9394-9441 Sentence denotes 29 Pratensein −6.6 80 Isoferulic acid −5.4
T114 9442-9493 Sentence denotes 30 Hispidulin −6.6 81 Dihydrocaffeic acid −5.4
T115 9494-9538 Sentence denotes 31 Baicalein −6.5 82 Gentisic acid −5.3
T116 9539-9579 Sentence denotes 32 Apigenin −6.5 83 Pyrogallol −5.3
T117 9580-9629 Sentence denotes 33 Morin −6.5 84 4-Hydroxycinnamic acid −5.2
T118 9630-9678 Sentence denotes 34 Urolithin A −6.5 85 Resacetophenone −5.2
T119 9679-9724 Sentence denotes 35 Acacetin −6.5 86 Salicyclic acid −5.1
T120 9725-9772 Sentence denotes 36 Pelargonidin −6.5 87 Syringic acid −5.1
T121 9773-9823 Sentence denotes 37 Irilone −6.5 88 2-Hydroxybenzoic acid −5.1
T122 9824-9867 Sentence denotes 38 Naringenin −6.5 89 Gallic acid −5.0
T123 9868-9922 Sentence denotes 39 Pinocembrin −6.5 90 3-Hydroxybenzoic acid −5.0
T124 9923-9977 Sentence denotes 40 Kaempferide −6.5 91 4-Hydroxybenzoic acid −5.0
T125 9978-10016 Sentence denotes 41 Malvidin −6.5 92 Vanillin −5.0
T126 10017-10062 Sentence denotes 42 Luteolin −6.4 93 p-Coumeric acid −4.9
T127 10063-10107 Sentence denotes 43 Dalbergin −6.4 94 Vanillic acid −4.8
T128 10108-10143 Sentence denotes 44 Butein −6.4 95 Paeonol −4.8
T129 10144-10195 Sentence denotes 45 Biochanin A (1-) −6.4 96 Cinnamic acid −4.7
T130 10196-10243 Sentence denotes 46 Fustin −6.4 97 Protocatechuic acid −4.6
T131 10244-10295 Sentence denotes 47 5-Hydroxyflavone −6.4 98 4-Ethylphenol −4.5
T132 10296-10337 Sentence denotes 48 Pinostrobin −6.4 99 Catechol −4.5
T133 10338-10379 Sentence denotes 49 Pinobanksin −6.4 100 Tyrosol −4.5
T134 10380-10418 Sentence denotes 50 Datiscetin −6.3 101 GTP −7.9
T135 10419-10462 Sentence denotes 51 Galangin −6.3 102 Remdesivir −7.7
T136 10464-10470 Sentence denotes 2.1.3.
T137 10472-10507 Sentence denotes Docking studies using AutoDock Vina
T138 10508-10690 Sentence denotes The energy-minimized structure of all the natural polyphenols, remdesivir, and GTP were docked with the receptor (RdRp of SARS-CoV-2) using AutoDock Vina 1.1.2 (Trott & Olson, 2010).
T139 10691-10879 Sentence denotes The ligand files were further saved in PDBQT file format, a modified PDB format containing atomic charges, atom type definitions for ligands, and topological information (rotatable bonds).
T140 10880-11003 Sentence denotes A grid box (30 Å × 30 Å × 30 Å) centered at (121, 120, 125) Å for the SARS-CoV-2 RdRp, was used in the docking experiments.
T141 11004-11093 Sentence denotes After the receptor-ligand preparation, docking runs were started from the command prompt.
T142 11094-11218 Sentence denotes The lowest binding energy and best-docked conformation were considered as the ligand molecule with maximum binding affinity.
T143 11220-11226 Sentence denotes 2.1.4.
T144 11228-11255 Sentence denotes Protein-ligand interactions
T145 11256-11439 Sentence denotes LigPlot+ was used to investigate protein-ligand interactions for a given .pdb file containing the docked conformation and also the final simulated conformation (Wallace et al., 1995).
T146 11440-11535 Sentence denotes The LigPlot+ program self-generated schematic 2D representations of protein-ligand interaction.
T147 11536-11689 Sentence denotes The output file represents the intermolecular interactions and their strengths, including hydrogen bonds, hydrophobic contacts, and atom accessibilities.
T148 11690-11822 Sentence denotes H-bonds are shown in green dotted lines, whereas residues involved in hydrophobic interaction are represented in the red semicircle.
T149 11824-11828 Sentence denotes 2.2.
T150 11830-11860 Sentence denotes Molecular dynamics simulations
T151 11861-12137 Sentence denotes All-atom molecular dynamics (MD) simulations were performed on the best eight selected plant-derived natural polyphenols obtained from the molecular docking study along with remdesivir, a well-known RdRp inhibitor, for studying thermodynamic stability of the docked structure.
T152 12138-12183 Sentence denotes The pmemd.cuda module in AMBER18 (Case et al.
T153 12184-12305 Sentence denotes 2018) was used for conducting MD simulations, and all simulations were performed utilizing the graphics card, RTX 2080Ti.
T154 12306-12449 Sentence denotes We adopted the same protocol that was used in our earlier studies (Jonniya et al., 2019; Sk, Roy, Jonniya, et al., 2020; Sk, Roy, & Kar, 2020).
T155 12450-12595 Sentence denotes The receptor and small molecules were described by the Amber ff14SB (Maier et al., 2015) and GAFF2 (Wang et al., 2004) force field, respectively.
T156 12596-12729 Sentence denotes Ligands were assigned the AM1-BCC (Jakalian et al., 2002) atomic charges calculated using the antechamber (Wang et al., 2001) module.
T157 12730-12895 Sentence denotes The complexes were then solvated using an explicit TIP3P (Price & Brooks III, 2004) water model, and nearly 38124 water molecules were needed to solvate each system.
T158 12896-12991 Sentence denotes Subsequently, all solvated systems were neutralized by adding an appropriate number of Na+ ion.
T159 12992-13100 Sentence denotes All bond lengths, including hydrogen atoms, were constrained by the SHAKE algorithm (Kräutler et al., 2001).
T160 13101-13143 Sentence denotes This allows the usage of a 2 fs time-step.
T161 13144-13308 Sentence denotes The non-bonded cut-off was set to 8 Å and the long range electrostatic interactions were evaluated using the particle-mesh Ewald (PME) (Darden et al., 1993) method.
T162 13309-13436 Sentence denotes The temperature was kept at 300 K using the Langevin thermostat (Loncharich et al., 1992) with a collision frequency of 2 ps−1.
T163 13437-13542 Sentence denotes The system pressure was controlled by Berendsen’s Barostat (Berendsen et al., 1984) and fixed at 1.0 bar.
T164 13543-13593 Sentence denotes We used a time-step of 2.0 fs for all simulations.
T165 13594-13638 Sentence denotes Briefly, we used two stages of minimization.
T166 13639-13913 Sentence denotes Firstly, each complex was optimized by 500 steps of steepest descent followed by another 500 steps of conjugate gradient minimization, keeping all atoms of the complex restrained to their initial coordinate with a weak harmonic potential (force constant 2.0 kcal mol−1 Å−2).
T167 13914-14134 Sentence denotes The second stage of minimization was carried out without any restraints by performing 100 steps of steepest descent, followed by another 900 steps of conjugate gradient minimization to remove any residual steric clashes.
T168 14135-14291 Sentence denotes Subsequently, all systems were gradually heated from 0 K to 300 K at the NVT ensemble with a force constant of 2.0 kcal mol−1Å−2 acting on all solute atoms.
T169 14292-14366 Sentence denotes Next, 1.0 ns equilibration MD phase was carried out without any restraint.
T170 14367-14460 Sentence denotes Finally, we performed 150 ns production simulations for all four systems at the NPT ensemble.
T171 14461-14642 Sentence denotes Overall, we accumulated 15000 conformations for each simulation, and we used 500 snapshots from the last 50 ns trajectories for binding affinity estimation using the MM-PBSA scheme.
T172 14643-14749 Sentence denotes The trajectory analysis was done by the AmberTools19 CPPTRAJ (Roe & Cheatham III, 2013) module of Amber18.
T173 14751-14755 Sentence denotes 2.3.
T174 14757-14820 Sentence denotes Molecular mechanics Poisson-Boltzmann surface area calculations
T175 14821-15247 Sentence denotes The binding affinity of EGCG, TF1, TF3, TF2b, TF2a, hesperidin, myricetin, quercetagetin, and remdesivir against the SARS-CoV-2 RdRp, were calculated by the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) methodology (Jonniya & Kar, 2020; Kar, Seel, et al., 2007; Kar, Wei, et al., 2007; Kar et al., 2011; 2013; Kar & Knecht, 2012a, 2012b, 2012c, 2012d; Kollman et al., 2000; Roy et al., 2020; Wang et al., 2006).
T176 15248-15529 Sentence denotes The MM-PBSA scheme can briefly be described as follows: (1) ΔGbind=ΔH−TΔS≈ΔEMM+ΔGsolv−TΔS (2) ΔEMM=ΔEinternal+ΔEelec+ΔEvdW (3) ΔGsolv=ΔGpol+ΔGnp where ΔEMM, ΔGsolv, TΔS are the changes in molecular mechanical energy, solvation free energy, and conformational entropy, respectively.
T177 15530-15795 Sentence denotes Further, molecular mechanical energy is composed of ΔEinternal (bond, dihedral, and angle), ΔEelec (electrostatic) and ΔEvdW (van der Waals) and the change in desolvation free energy is composed of polar solvation (ΔGpol) and non-polar solvation free energy (ΔGnp).
T178 15796-15881 Sentence denotes The polar solvation free energy, ΔGpol, was calculated by the pbsa module of AMBER18.
T179 15882-15970 Sentence denotes Due to the high computational cost, we neglect the configurational entropy calculations.
T180 15971-16239 Sentence denotes Further, to understand the polyphenol-protein interaction more closely, the interaction energy was decomposed into the contributions from each residue of the protein by using the molecular mechanics generalized Born surface area (MM-GBSA) scheme (Gohlke et al., 2003).
T181 16241-16245 Sentence denotes 2.4.
T182 16247-16260 Sentence denotes ADMET studies
T183 16261-16384 Sentence denotes The in-silico pharmacological studies of EGCG, TF2a, TF2b, TF3, and remdesivir were predicted based on their ADMET profile.
T184 16385-16574 Sentence denotes The ADMET studies (absorption, distribution, metabolism, elimination, and toxicity) were predicted using the pkCSM tool (http://biosig.unimelb.edu.au/pkcsm/prediction) (Pires et al., 2015).
T185 16575-16721 Sentence denotes The canonical SMILE molecular structures of the above-mentioned compounds were retrieved from the PubChem database (www.pubchem.ncbi.nlm.nih.gov).
T186 16723-16727 Sentence denotes 2.5.
T187 16729-16756 Sentence denotes Molecular target prediction
T188 16757-16833 Sentence denotes Natural compounds interact with a large number of proteins, enzymes, lipids.
T189 16834-16934 Sentence denotes This interaction plays a crucial role in elucidating the molecular mechanism of the small molecules.
T190 16935-17030 Sentence denotes So, it is important to identify the molecular targets for new molecules (Gfeller et al., 2014).
T191 17031-17273 Sentence denotes Swiss Target Prediction website (http://www.swisstargetprediction.ch/index.php) was logged on, and canonical SMILE molecular structures of remdesivir, EGCG, TF2a, TF2b, and TF3 were entered in the search bar option, and results were analyzed.
T192 17275-17277 Sentence denotes 3.
T193 17279-17301 Sentence denotes Results and discussion
T194 17303-17307 Sentence denotes 3.1.
T195 17309-17335 Sentence denotes Molecular docking analysis
T196 17337-17343 Sentence denotes 3.1.1.
T197 17345-17465 Sentence denotes The binding mode analysis and predicted binding affinity calculations of natural polyphenols against the SARS-CoV-2 RdRp
T198 17466-17560 Sentence denotes Herein, we investigated our natural polyphenol library against RdRp of the SARS-CoV-2 (PDB ID:
T199 17561-17588 Sentence denotes 6M71) by molecular docking.
T200 17589-17731 Sentence denotes The best conformation of the natural polyphenols was docked against the SARS-CoV-2 RdRp, and resulting binding energies are listed in Table 1.
T201 17732-17915 Sentence denotes Polyphenols exhibiting binding energy of −7.0 kcal/mol or lower (eight polyphenols) against RdRp of the SARS-CoV-2 are listed in Table 2 along with the ligand-amino acid interactions.
T202 17916-18053 Sentence denotes Control compounds, GTP and remdesivir, exhibited the binding energy of −7.9 and −7.7 kcal/mol, respectively, against the SARS-CoV-2 RdRp.
T203 18054-18397 Sentence denotes Eight polyphenols displayed significantly higher binding affinity among the selected hundred natural polyphenols docked against the SARS-CoV-2 RdRp, with binding energies of TF3, TF2b, TF1, TF2a, hesperidin, EGCG, myricetin and quercetagetin as −9.9, −9.6, −9.6, −9.3, −8.8, −7.3, −7.2 and −7.0 kcal/mol, respectively (highlighted in Table 1).
T204 18398-18597 Sentence denotes Further, 2D LigPlot+ representation of RdRp and the above-mentioned eight polyphenols reveal the stable network of molecular interactions (see Table 2 and Figure S1 in the Supplementary Information).
T205 18598-18606 Sentence denotes Table 2.
T206 18608-18708 Sentence denotes Ligand-amino acid interactions of top eight scoring natural polyphenols against the SARS-CoV-2 RdRp.
T207 18709-18711 Sentence denotes S.
T208 18712-18715 Sentence denotes No.
T209 18717-18813 Sentence denotes Compound name Binding energy (kcal/mol) No. of non-covalent interactions Involved amino acids
T210 18814-18932 Sentence denotes 1 TF3 −9.9 17 W617, K551, S549, D623, R836, S814, E811, F812, C813, D761, D618, S759, Y619, C622, R553, K621, D760
T211 18933-19028 Sentence denotes 2 TF2b −9.6 13 K551, Y619, D760, K798, W617, W800, D761, F812, C813, E811, D618, S549, A550
T212 19029-19117 Sentence denotes 3 TF1 −9.6 12 W617, D761, D760, Y619, R553, K621, P620, F793, D164, S795, K798, D618
T213 19118-19219 Sentence denotes 4 TF2a −9.3 14 C813, F812, D761, D760, D618, K798, K551, A550, S549, K621, Y619, W800, W617, E811
T214 19220-19321 Sentence denotes 5 Hesperidin −8.8 13 Y619, D618, K798, S795, M794, P793, D164, V166, P620, K621, D623, R555, Y455
T215 19322-19392 Sentence denotes 6 EGCG −7.3 9 D623, Y619, K621, S795, C622, D618, M794, P620, K798
T216 19393-19475 Sentence denotes 7 Myricetin −7.2 10 W617, W800, D760, E811, K798, D618, Y619, C622, D761, F812
T217 19476-19549 Sentence denotes 8 Quercetagetin −7.0 8 R553, K545, K621, D623, C622, D760, P620, Y619
T218 19550-19661 Sentence denotes 9 Remdesivir (Control) −7.7 13 R553, K621, C622, D760, E811, W800, K798, P620, Y455, R624, Y619, D618, D761
T219 19662-20001 Sentence denotes 10 GTP (Control) −7.9 15 R624, T556, D623, D760, Y619, C622, K621, D452, A554, R553, Y455, R555, D761, D618, P620 In addition to remdesivir, here we observed that eight dietary polyphenols (TF1, TF2a, TF2b, TF3, hesperidin, EGCG, myricetin and quercetagetin) have significant potential to function as inhibitors of the SARS-CoV-2 RdRp.
T220 20002-20309 Sentence denotes The top-eight scoring ligands for the SARS-CoV-2 RdRp (as highlighted in Table 1) suggest that these set of natural polyphenols can strongly bind to the catalytic site of the SARS-CoV-2 RdRp and are expected to inhibit the RdRp activity, and thus blocking the replication and preventing viral transcription.
T221 20310-20462 Sentence denotes Many reports suggest polyphenols have low systemic toxicity, and they are highly beneficial for human health (Bhardwaj et al., 2020; Cory et al., 2018).
T222 20463-20691 Sentence denotes TF1 and its gallate derivatives, collectively known as black tea polyphenols, previously have shown to exert antiviral activity against many viruses such as hepatitis virus and influenza A and B viruses (Chowdhury et al., 2018).
T223 20692-20864 Sentence denotes Hesperidin is also known to possess antiviral activity by altering the immune system mainly via regulating interferons in the influenza A virus (Randall & Goodbourn, 2008).
T224 20865-21015 Sentence denotes EGCG, a major green tea polyphenol, has several pharmacological properties, including antiviral activity (Carneiro et al., 2016; Moon & Morris, 2007).
T225 21016-21131 Sentence denotes Similarly, myricetin has also been found to act as an inhibitor of the SARS coronavirus helicase (Yu et al., 2012).
T226 21132-21254 Sentence denotes Quercetagetin also showed strong hepatitis C virus replication inhibitory activity in vitro (Ahmed-Belkacem et al., 2014).
T227 21255-21447 Sentence denotes Thus, the set dietary polyphenols identified in the present study could be used as repurposed drugs for the treatment of the SARS-CoV-2 infection with further in-vitro and in-vivo validations.
T228 21449-21453 Sentence denotes 3.2.
T229 21455-21489 Sentence denotes Molecular dynamics (MD) simulation
T230 21491-21497 Sentence denotes 3.2.1.
T231 21499-21547 Sentence denotes Thermodynamic stability and flexibility analysis
T232 21548-21832 Sentence denotes The 150 ns production simulations carried out for nine systems (complex of remdesivir, EGCG, TF1, TF2a, TF2b, TF3, hesperidin, myricetin, and quercetagetin with the SARS-CoV-2 RdRp) were stable on the basis of the potential energy and total energy (data not shown) of those complexes.
T233 21833-22014 Sentence denotes Subsequently, the root-mean-square deviations (RMSDs) of backbone atoms relative to their respective initial positions were calculated for each complex and are shown in Figure 3(A).
T234 22015-22182 Sentence denotes It is evident from Figure 3(A) that all the nine studied systems drifted from their initial positions during the first 50 ns, and after that, they reached equilibrium.
T235 22183-22466 Sentence denotes The average RMSD values were estimated to be 2.30 Å, 2.45 Å, 1.87 Å, 2.28 Å, 1.68 Å, 2.47 Å, 1.90 Å, 2.03 Å and 1.88 Å for RdRp/remdesivir, RdRp/EGCG, RdRp/TF3, RdRp/TF2b, RdRp/TF2a, RdRp/myricetin, RdRp/quercetagetin, RdRp/hesperidin, and RdRp/TF1 complexes, respectively (Table 3).
T236 22467-22568 Sentence denotes The least deviation was observed for RdRp/TF2a, while RdRp/myricetin displayed the highest deviation.
T237 22569-22790 Sentence denotes We also investigated structural variations in the binding site, including all amino acids that fall within a radius of 5 Å from the inhibitor, and the same trend was observed (Figure S2A in the Supplementary Information).
T238 22791-22849 Sentence denotes Overall, this suggests the convergence of our simulations.
T239 22850-23073 Sentence denotes Figure 3. (A) Time evolution of root-mean-square deviations (RMSDs) of backbone atoms and (B) the root-mean-square fluctuations (RMSFs) of Cα atoms of nine complexes relative to their respective energy minimized structure.
T240 23074-23082 Sentence denotes Table 3.
T241 23084-23203 Sentence denotes The average backbone RMSD, radius of gyration (RoG), and solvent accessible surface area (SASA) for all nine complexes.
T242 23204-23272 Sentence denotes The data are reported as average ± standard error of the mean (SEM).
T243 23273-23309 Sentence denotes System RMSD (Å) RoG (Å) SASA (Å2)
T244 23310-23370 Sentence denotes RdRp/Remdesivir 2.30 ± 0.03 29.96 ± 0.02 34973.20 ± 91.56
T245 23371-23425 Sentence denotes RdRp/EGCG 2.45 ± 0.05 29.52 ± 0.06 35026.03 ± 63.52
T246 23426-23479 Sentence denotes RdRp/TF3 1.87 ± 0.02 29.60 ± 0.01 34080.16 ± 53.41
T247 23480-23534 Sentence denotes RdRp/TF2b 2.28 ± 0.01 29.86 ± 0.02 35462.92 ± 50.40
T248 23535-23590 Sentence denotes RdRp/TF2a 1.68 ± 0.02 29.75 ± 0.02 34312.55 ± 112.89
T249 23591-23651 Sentence denotes RdRp/Myricetin 2.47 ± 0.03 29.88 ± 0.01 35395.35 ± 104.67
T250 23652-23715 Sentence denotes RdRp/Quercetagetin 1.90 ± 0.03 29.84 ± 0.01 34618.65 ± 51.25
T251 23716-23776 Sentence denotes RdRp/Hesperidin 2.03 ± 0.04 29.74 ± 0.02 34554.08 ± 47.25
T252 23777-24061 Sentence denotes RdRp/TF1 1.88 ± 0.03 29.86 ± 0.01 34420.69 ± 56.90 Next, we investigated the structural stability of remdesivir and eight polyphenols by estimating the temporal RMSDs of heavy atoms relative to their respective initial coordinates (see Figure S2B in the Supplementary Information).
T253 24062-24215 Sentence denotes It is evident from Figure S2B that EGCG, myricetin, quercetagetin, TF1, TF3 displayed a rigid behavior in the bound form with an average RMSD of < 1.0 Å.
T254 24216-24378 Sentence denotes However, remdesivir, TF2a, TF2b and hesperidin showed higher fluctuations as compared to the abovementioned polyphenols, and an average RMSD of > 2.0 Å was noted.
T255 24379-24533 Sentence denotes To identify the regions which are flexible, the root-mean-square fluctuations (RMSFs) of Cα atoms of each residue are calculated and shown in Figure 3(B).
T256 24534-24705 Sentence denotes From this analysis, we can get a better insight into what extent the binding of remdesivir and natural polyphenols affects the residual flexibility of RdRp (mainly Nsp12).
T257 24706-24800 Sentence denotes Figure 3(B) indicates that RdRp/remdesivir and RdRp-polyphenols shared a similar RMSF pattern.
T258 24801-24916 Sentence denotes Notable dynamic fluctuations were located in the non-active site domain, including both N-terminals and C-terminal.
T259 24917-25050 Sentence denotes Regions around Asn150, Asp260, Arg305, Asn360, and Phe440 are found to be more flexible compared to the other area for all complexes.
T260 25051-25375 Sentence denotes The binding pocket residues, such as Asp452, Lys545, Lys551, Tyr455, Arg553, Ala554, Arg555, Thr556, Asp618, Tyr619, pro620, Lys621, Cys622, Asp623 Arg624, Asn691, Asp760, Asp761, Phe793, Met794, Ser795, Lys798, Trp800, Glu811, Phe812, and Ser814 exhibited considerably low fluctuations for all the RdRp-inhibitor complexes.
T261 25376-25519 Sentence denotes In the case of RdRp/TF3 and RdRp/TF2a, the binding site residues displayed lesser fluctuations compared to the other RdRp-polyphenol complexes.
T262 25520-25624 Sentence denotes This suggests that TF3 and TF2a are likely to be bound to RdRp more strongly than the other polyphenols.
T263 25625-25816 Sentence denotes Since the radius of gyration (RoG) helps us to understand the protein structural compactness, RoG of each complex was monitored and represented in Figure S3A in the Supplementary Information.
T264 25817-26057 Sentence denotes The average values of RoG are 29.96 Å, 29.52 Å, 29.60 Å, 29.86 Å, 29.75 Å, 29.88 Å, 29.84 Å, 29.74 Å and 29.86 Å for RdRp complexed with remdesivir, EGCG, TF3, TF2b, TF2a, myricetin, quercetagetin, hesperidin and TF1 respectively (Table 3).
T265 26058-26142 Sentence denotes This suggests that the structural compactness remained unchanged during simulations.
T266 26143-26337 Sentence denotes Finally, the solvent-accessible surface area (SASA) was also explored, and the time evolution of SASA for four RdRp-polyphenol complexes are shown in Figure S3B in the Supplementary Information.
T267 26338-26389 Sentence denotes The average values of SASA are reported in Table 3.
T268 26390-26501 Sentence denotes Binding of an inhibitor to the substrate changes SASA and sometimes could greatly affect the protein structure.
T269 26502-26626 Sentence denotes Here, a relatively higher SASA value was obtained for RdRp/TF2b (35462.9 Å2) compared to the other RdRp/inhibitor complexes.
T270 26627-26704 Sentence denotes On the other hand, the lowest SASA value was noted for RdRp/TF3 (34080.2 Å2).
T271 26705-26798 Sentence denotes Thus, it can be suggested that the binding of TF3 could potentially reduce protein expansion.
T272 26800-26806 Sentence denotes 3.2.2.
T273 26808-26836 Sentence denotes Binding free energy analysis
T274 26837-27070 Sentence denotes We predicted the binding free energy of all nine complexes by utilizing the MM-PBSA scheme, and four polyphenols, namely EGCG, TF3, TF2b, and TF2a, displayed a higher estimated affinity compared to remdesivir as depicted in Figure 4.
T275 27071-27170 Sentence denotes Various components of the binding free energy of EGCG, TF3, TF2b, and TF2a are reported in Table 4.
T276 27171-27313 Sentence denotes The remaining four polyphenols which showed lower estimated affinity compare to remdesivir are shown in Table S2 in Supplementary Information.
T277 27314-27539 Sentence denotes It can be noted from Figure 4 that the intermolecular van der Waals (ΔEvdW) and electrostatic (ΔEelec) terms are favorable for the ligand binding, whereas the desolvation of polar groups (ΔGpol) opposes the complex formation.
T278 27540-27621 Sentence denotes Non-polar solvation free energy (ΔGnp) is favorable to the binding for all cases.
T279 27622-27705 Sentence denotes A similar trend was observed in our earlier study (Sk, Roy, Jonniya, et al., 2020).
T280 27706-27715 Sentence denotes Figure 4.
T281 27717-28004 Sentence denotes Energy components (kcal/mol) for the binding of remdesivir and four polyphenols to RdRp receptor. ΔEvdW, van der Waals interaction; ΔEele, electrostatic interaction in the gas phase; ΔGpol, polar solvation energy; ΔGnp, non-polar solvation energy, and ΔGbind, estimated binding affinity.
T282 28005-28013 Sentence denotes Table 4.
T283 28015-28139 Sentence denotes Energetic components of the binding free energy of RdRp and natural polyphenols along with remdesivir complexes in kcal/mol.
T284 28140-28178 Sentence denotes Data are represented as average ± SEM.
T285 28179-28224 Sentence denotes Components Remdesivir EGCG TF3 TF2b TF2a
T286 28225-28305 Sentence denotes ΔEvdW −31.85 ± 0.15 −25.11 ± 0.18 −37.82 ± 0.21 −30.66 ± 0.23 −22.55 ± 0.19
T287 28306-28388 Sentence denotes ΔEelec −98.40 ± 0.70 −69.38 ± 0.73 −123.63 ± 0.88 −47.18 ± 0.64 −95.28 ± 1.27
T288 28389-28466 Sentence denotes ΔGpol 109.97 ± 0.57 71.62 ± 0.48 124.47 ± 0.58 55.01 ± 0.49 94.94 ± 1.10
T289 28467-28541 Sentence denotes ΔGnp −4.29 ± 0.01 −4.15 ± 0.01 −5.29 ± 0.01 −3.91 ± 0.01 −4.28 ± 0.02
T290 28542-28620 Sentence denotes aΔGsolv 105.68 ± 0.57 67.47 ± 0.48 119.18 ± 0.58 51.1 ± 0.49 90.66 ± 1.10
T291 28621-28701 Sentence denotes bΔGpol + elec 11.57 ± 0.90 2.24 ± 0.87 0.84 ± 1.05 7.83 ± 0.80 −0.34 ± 1.68
T292 28702-28785 Sentence denotes cΔEMM −130.25 ± 0.71 −94.49 ± 0.75 −161.45 ± 0.90 −77.84 ± 0.68 −117.83 ± 1.28
T293 28786-28870 Sentence denotes ΔGbindSim −24.57 ± 0.91 −27.02 ± 0.89 −42.27 ± 1.07 −26.74 ± 0.83 −27.17 ± 1.69
T294 28871-28896 Sentence denotes a ΔGsolv = ΔGnp + ΔGpol,
T295 28897-28930 Sentence denotes b ΔGpol + elec = ΔEelec + ΔGpol,
T296 28931-28956 Sentence denotes c ΔEMM = ΔEvdW + ΔEelec.
T297 28957-29126 Sentence denotes It is evident from Table 4 that for all complexes, ΔEvdW varies between −22.55 kcal/mol and −37.82 kcal/mol while ΔEelec ranges from −47.18 kcal/mol to −123.63 kcal/mol.
T298 29127-29573 Sentence denotes Furthermore, in the cases of RdRp/remdesivir, RdRp/EGCG, RdRp/TF3, and RdRp/TF2b, ΔEele is over-compensated by the desolvation energy (ΔGpol), indicating that the sum of these two components, ΔGpol + elec, is unfavorable to the binding and varies between 0.84 kcal/mol and 11.57 kcal/mol (see Table 4) and similar results are found for RdRp/myricetin, RdRp/quercetagetin, RdRp/hesperidin, and RdRp/TF1 (see Table S2 in Supplementary Information).
T299 29574-29692 Sentence denotes In contrast, in the case of RdRp/TF2a, ΔGpol + elec, is favorable to the complexation (ΔGpol + elec = −0.34 kcal/mol).
T300 29693-29845 Sentence denotes Overall, this suggests that the complex formation is mainly driven by the van der Waals interactions between polyphenols as well as remdesivir and RdRp.
T301 29846-29950 Sentence denotes Therefore, hydrophobic residues in the binding pocket played a crucial role in the complexation process.
T302 29951-30267 Sentence denotes The estimated binding free energy (ΔGbind) of remdesivir, EGCG, TF3, TF2b, and TF2a were −24.57, −27.02, −42.27, −26.74 and −27.17 kcal/mol, respectively (Table 4) and myricetin, quercetagetin, hesperidin and TF1 show lower binding affinity compared to that of remdesivir (Table S2 in the Supplementary Information).
T303 30268-30357 Sentence denotes This suggests that polyphenol TF3 binds most strongly to RdRp, followed by TF2a and EGCG.
T304 30358-30465 Sentence denotes The potency of the five inhibitors decreases in the following order: TF3 > TF2a > EGCG > TF2b > remdesivir.
T305 30466-30595 Sentence denotes TF3 binds most strongly to RdRp because both ΔEvdW and ΔEelec are more favorable to the binding compared to the other inhibitors.
T306 30596-30856 Sentence denotes Similarly, TF2a binds more strongly to RdRp compared to EGCG or TF2b because ΔGpol + elec is favorable for TF2a (ΔGpol + elec = −0.34 kcal/mol) while it is found to be unfavorable for EGCG (ΔGpol + elec = 2.24 kcal/mol) and TF2b (ΔGpol + elec = 7.83 kcal/mol).
T307 30858-30864 Sentence denotes 3.2.3.
T308 30866-30908 Sentence denotes Essential residues for polyphenols binding
T309 30909-31118 Sentence denotes Further, to gain a deeper insight into the best four RdRp/polyphenols and remdesivir interaction pattern, the total binding free energy was decomposed into polyphenols-residue pair based on the MM-GBSA scheme.
T310 31119-31309 Sentence denotes The approach of per-residue based contributions is useful to determine the binding mechanisms of an inhibitor at an atomistic level, and it also reveals the individual residue contributions.
T311 31310-31438 Sentence denotes The different energy contributions from the backbone and side-chain of each residue are shown in Figure 5 and listed in Table 5.
T312 31439-31448 Sentence denotes Figure 5.
T313 31450-31596 Sentence denotes Decomposition of the binding free energy into contributions from individual residues for RdRp complexed with remdesivir, EGCG, TF3, TF2b and TF2a.
T314 31597-31605 Sentence denotes Table 5.
T315 31607-31743 Sentence denotes Per-residue based decomposition of binding free energy for the complex of remdesivir, EGCG, TF3, TF2a and TF2b with the SARS-CoV-2 RdRp.
T316 31744-31807 Sentence denotes Residue TvdW Telec Tpol Tnp Tside_chain Tbackbone Ttotal
T317 31808-31823 Sentence denotes RdRp/Remdesivir
T318 31824-31879 Sentence denotes Asp761 1.05 −21.73 18.81 −0.14 −1.82 −0.19 −2.01
T319 31880-31933 Sentence denotes Lys798 −2.74 −4.28 5.74 −0.47 −1.76 0.01 −1.75
T320 31934-31988 Sentence denotes Pro620 −1.42 −1.15 1.16 −0.18 −1.26 −0.33 −1.59
T321 31989-32043 Sentence denotes Asp760 −0.57 −4.27 4.24 −0.12 −0.20 −0.52 −0.72
T322 32044-32097 Sentence denotes Arg553 −2.07 −3.71 5.61 −0.51 −0.76 0.08 −0.68
T323 32098-32107 Sentence denotes RdRp/EGCG
T324 32108-32161 Sentence denotes Asp452 1.65 −16.48 9.85 −0.08 −5.15 0.09 −5.06
T325 32162-32215 Sentence denotes Arg553 −3.83 −4.84 6.59 −0.59 −2.68 0.01 −2.67
T326 32216-32270 Sentence denotes Pro620 −1.64 −0.41 0.51 −0.33 −1.62 −0.25 −1.87
T327 32271-32324 Sentence denotes Asp618 0.49 −8.14 6.66 −0.09 −1.13 −0.05 −1.08
T328 32325-32379 Sentence denotes Lys621 −2.26 −5.12 6.92 −0.50 −0.87 −0.09 −0.96
T329 32380-32388 Sentence denotes RdRp/TF3
T330 32389-32444 Sentence denotes Asp761 2.52 −30.13 22.11 −0.25 −5.54 −0.21 −5.75
T331 32445-32501 Sentence denotes Arg836 −0.83 −14.95 12.29 −0.37 −3.85 −0.01 −3.86
T332 32502-32556 Sentence denotes Arg555 −5.80 −4.00 7.29 −0.70 −2.98 −0.23 −3.21
T333 32557-32611 Sentence denotes Thr556 −0.20 −3.96 2.44 −0.13 −0.21 −1.64 −1.85
T334 32612-32666 Sentence denotes Ile548 −1.03 −0.08 0.12 −0.13 −0.65 −0.47 −1.12
T335 32667-32720 Sentence denotes Ser814 −1.67 0.09 0.78 −0.08 −0.48 −0.40 −0.88
T336 32721-32775 Sentence denotes Val557 −0.65 −0.16 0.17 −0.24 −0.65 −0.23 −0.88
T337 32776-32785 Sentence denotes RdRp/TF2b
T338 32786-32840 Sentence denotes His816 −3.00 −0.81 1.69 −0.32 −1.63 −0.81 −2.44
T339 32841-32895 Sentence denotes Asp833 −1.29 −0.23 0.46 −0.18 −0.21 −1.03 −1.24
T340 32896-32950 Sentence denotes Tyr877 −0.92 −2.06 2.06 −0.27 −0.43 −0.76 −1.19
T341 32951-33003 Sentence denotes Glu811 0.22 −9.24 8.11 −0.13 −2.07 1.03 −1.04
T342 33004-33058 Sentence denotes His810 −1.88 −0.41 1.66 −0.34 −0.10 −0.85 −0.95
T343 33059-33113 Sentence denotes Tyr831 −1.51 −0.36 1.19 −0.13 −0.21 −0.60 −0.81
T344 33114-33168 Sentence denotes Asn815 −0.60 −0.27 0.09 −0.01 −0.25 −0.54 −0.79
T345 33169-33178 Sentence denotes RdRp/TF2a
T346 33179-33234 Sentence denotes Asp618 2.63 −20.71 13.40 −0.17 −4.84 −0.01 −4.85
T347 33235-33289 Sentence denotes Arg553 −3.80 −6.52 7.55 −0.69 −2.68 −0.78 −3.46
T348 33290-33344 Sentence denotes Lys551 −2.23 −0.80 2.23 −0.45 −0.84 −0.41 −1.25
T349 33345-33399 Sentence denotes Arg555 −1.33 −0.62 1.05 −0.27 −1.12 −0.05 −1.17
T350 33400-33682 Sentence denotes Glu167 0.42 −6.82 5.92 −0.12 −0.61 0.01 −0.60 As shown in Figure 5, it was observed that residues favoring the binding of the polyphenols with RdRp include Asp452, Arg553, Arg555, Val557, Asp618, Pro620, Lys621, Asp623, Arg624, Asp760, Asp761, and Glu811, Asp833, and Arg836.
T351 33683-33807 Sentence denotes Most of these residues are located in the binding site of RdRp and can form direct contacts with polyphenols and remdesivir.
T352 33808-34184 Sentence denotes Figure 5 shows that amino acids Pro620, Asp761 and Lys798 for RdRp/remdesivir; Asp452, Arg553, Pro620 and Lys621 for RdRp/EGCG; Ile548, Arg555, Thr556, Asp761 and Arg836 for RdRp/TF3; Glu811, His816, Asp833 and Tyr877 for RdRp/TF2b; Lys551, Arg553, Arg555 and Asp618 for RdRp/TF2a contributed more favorably towards the binding by contributing more than −1.0 kcal/mol in size.
T353 34185-34365 Sentence denotes To complement the energetic analysis, we performed MD trajectory-based hydrogen bond (h-bond) analysis for all five complexes, and the h-bonds with occupancy are listed in Table 6.
T354 34366-34474 Sentence denotes The h-bonds were determined by setting the acceptor-donor distance of ≤ 3.5 Å, and the angle cut off ≥ 1200.
T355 34475-34539 Sentence denotes Important h-bonds between RdRp-inhibitors are shown in Figure 6.
T356 34540-34663 Sentence denotes In the case of RdRp/remdesivir, key residues involved in the hydrogen bonding are Asp761, Asp760, and Ser759, respectively.
T357 34664-34821 Sentence denotes Asp760 is found to form two h-bonds with remdesivir (Asp760@OD2 - Lig@O7, Asp760@OD2 - Lig@O6) with an occupancy of more than 15% (see Table 6 and Figure 6).
T358 34822-34954 Sentence denotes In the case of RdRp/EGCG, both Asp618 and Asp760 form two h-bonds with the ligand with an occupancy in the range of 16.09 to 30.17%.
T359 34955-35202 Sentence denotes On the other hand, Asp761 form an h-bond with TF3 (Asp761@OD1 - Lig@O11) with an occupancy of 69.84%, while Arg836 forms two h-bonds with the ligand (Arg836@NH2 - Lig@O14, Arg836@NE - Lig@O14) with an occupancy of 52.66%, and 48.70%, respectively.
T360 35203-35355 Sentence denotes Glu811, Thr556 and Asp761 also formed h-bonds with the ligand during our simulations with an occupancy varying in the range of 44% to 58% (see Table 6).
T361 35356-35537 Sentence denotes In the case of RdRp/TF2b, Glu811 is found to form two strong h–bonds with the ligand (Glu811@OE1 – Lig@O7, Glu811@OE2 – Lig@O7) with an occupancy of 22.45% and 18.89%, respectively.
T362 35538-35707 Sentence denotes On the other hand, it can be observed from Table 6 that Pro832 and Tyr877 form strong h-bonds (Pro832@O -Lig@O8 and Lig@O10 -Tyr877@OH) with increased occupancy (> 24%).
T363 35708-35898 Sentence denotes Finally, in the case of RdRp/TF2a, Asp618 is found to form two strong h-bonds with the TF2a (Asp618@OD1 – Lig@O10, Asp618@OD1 – Lig@O11) with an occupancy of 38.68% and 38.38%, respectively.
T364 35899-35975 Sentence denotes Asp760 also forms a h-bond (Asp760@O – Lig@O11) with an occupancy of 20.83%.
T365 35976-35985 Sentence denotes Figure 6.
T366 35987-36049 Sentence denotes Five main hydrogen bond interactions between ligands and RdRp.
T367 36050-36058 Sentence denotes Table 6.
T368 36060-36273 Sentence denotes Main hydrogen bond interactions formed by RdRp with remdesivir and polyphenols along with the corresponding average distance and percentage of occupancy determined using the trajectories of production simulations.
T369 36274-36295 Sentence denotes Acceptor Donor Avg.
T370 36296-36323 Sentence denotes Distance (Å) Occupancy (%)
T371 36324-36339 Sentence denotes RdRp/Remdesivir
T372 36340-36371 Sentence denotes Asp760@OD2 Lig@O7 2.66 19.46
T373 36372-36403 Sentence denotes Asp761@OD1 Lig@O7 2.65 17.70
T374 36404-36435 Sentence denotes Asp761@OD2 Lig@O6 2.63 16.86
T375 36436-36467 Sentence denotes Asp760@OD2 Lig@O6 2.65 16.65
T376 36468-36498 Sentence denotes Lig@O6 Ser759@OG 2.80 11.63
T377 36499-36530 Sentence denotes Asp760@OD1 Lig@O7 2.66 10.59
T378 36531-36540 Sentence denotes RdRp/EGCG
T379 36541-36572 Sentence denotes Asp618@OD1 Lig@O5 2.61 30.13
T380 36573-36604 Sentence denotes Asp618@OD1 Lig@O6 2.61 29.28
T381 36605-36636 Sentence denotes Asp618@OD2 Lig@O5 2.61 18.25
T382 36637-36668 Sentence denotes Asp618@OD2 Lig@O6 2.61 17.38
T383 36669-36700 Sentence denotes Asp760@OD1 Lig@O5 2.63 16.09
T384 36701-36732 Sentence denotes Tyr455@OH Lig@O11 2.83 10.97
T385 36733-36741 Sentence denotes RdRp/TF3
T386 36742-36774 Sentence denotes Asp761@OD1 Lig@O11 2.61 69.84
T387 36775-36805 Sentence denotes Glu811@O Lig@O10 2.76 58.43
T388 36806-36835 Sentence denotes Thr556@O Lig@O3 2.72 56.95
T389 36836-36868 Sentence denotes Lig@O14 Arg836@NH2 2.83 52.66
T390 36869-36900 Sentence denotes Lig@O14 Arg836@NE 2.86 48.70
T391 36901-36933 Sentence denotes Asp761@OD2 Lig@O20 2.62 44.51
T392 36934-36943 Sentence denotes RdRp/TF2b
T393 36944-36973 Sentence denotes Pro832@O Lig@O8 2.77 26.31
T394 36974-37005 Sentence denotes Lig@O11 Tyr877@OH 2.75 24.39
T395 37006-37037 Sentence denotes Glu811@OE1 Lig@O7 2.65 22.45
T396 37038-37069 Sentence denotes Glu811@OE2 Lig@O7 2.65 18.89
T397 37070-37101 Sentence denotes Asp833@OD2 Lig@O8 2.65 12.01
T398 37102-37133 Sentence denotes Asn874@OD1 Lig@O11 2.68 8.58
T399 37134-37143 Sentence denotes RdRp/TF2a
T400 37144-37176 Sentence denotes Asp618@OD1 Lig@O10 2.59 38.68
T401 37177-37209 Sentence denotes Asp618@OD1 Lig@O11 2.62 38.38
T402 37210-37240 Sentence denotes Asp760@O Lig@O11 2.70 20.83
T403 37241-37273 Sentence denotes Asp618@OD2 Lig@O11 2.62 16.59
T404 37274-37306 Sentence denotes Asp618@OD2 Lig@O10 2.58 16.49
T405 37307-37562 Sentence denotes Asp618@OD1 Lig@O15 2.67 16.37 Finally, we supplemented the above results by analyzing the final conformation of each production simulation with the help of 2D LigPlot+ software, and different h-bonds and hydrophobic interactions were shown in Figure 7.
T406 37563-37685 Sentence denotes Hydrogen bonds are depicted in green dotted lines, while red semicircle residues are involved in hydrophobic interactions.
T407 37686-37851 Sentence denotes For the RdRp/remdesivir complex, Figure 7(A) displayed nine hydrophobic interactions with Lys545, Ala547, Ser549, Arg553, Val557, Asp684, Ser759, Ser814, and Arg836.
T408 37852-37965 Sentence denotes This large number of interactions account for the high stability and good binding affinity of remdesivir to RdRp.
T409 37966-38062 Sentence denotes EGCG formed hydrophobic interactions with Lys551, Ala554, Arg553, Arg624, Pro620, (Figure 7(B)).
T410 38063-38224 Sentence denotes In the case of TF3, eight hydrophobic interactions with His439, Ile548, Ser814, Phe812, Val557, Ser549, Tyr619 and Arg555 were formed as revealed by Figure 7(C).
T411 38225-38368 Sentence denotes Figure 7(D) shows that seven hydrophobic interactions with Asp833, His816, Pro832, Gln815, His872, His810 and Ser434 were formed for RdRp/TF2b.
T412 38369-38474 Sentence denotes Finally, Figure 7(E) shows that RdRp/TF2a formed hydrophobic interactions with Arg555, Ala554 and Lys551.
T413 38475-38641 Sentence denotes Overall, TF3 has a higher binding affinity toward RdRp compared to the other polyphenols due to a larger number of stable hydrogen bonds and hydrophobic interactions.
T414 38642-38651 Sentence denotes Figure 7.
T415 38653-38776 Sentence denotes The RdRp-ligands interaction profile for (A) RdRp/remdesivir, (B) RdRp/EGCG, (C) RdRp/TF3, (D) RdRp/TF2b and (E) RdRp/TF2a.
T416 38777-38838 Sentence denotes The polyphenols and remdesivir are shown in balls and sticks.
T417 38839-38960 Sentence denotes Hydrogen bonds are depicted in green dotted lines, and red semicircles residues are involved in hydrophobic interactions.
T418 38962-38966 Sentence denotes 3.3.
T419 38968-39063 Sentence denotes Prediction of the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile
T420 39064-39354 Sentence denotes In addition to testing the physiochemical efficiency of a given molecule to inhibit the target protein, other parameters such as absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the inhibitor play a critical role on demonstrating the likelihood of success of a drug.
T421 39355-39603 Sentence denotes Utilization of in-silico ADMET profiling, in combination with in vivo and in vitro predictions in the initial stage of the screening process, can significantly fasten the drug discovery process by minimizing the number of potential safety problems.
T422 39604-39847 Sentence denotes Hence, we performed a detailed ADMET profiling to evaluate the drug likeliness of the four polyphenols: EGCG, TF2a, TF2b, TF3 that exhibited the highest score from the MD simulation and MM-PBSA study along with the positive control remdesivir.
T423 39848-40011 Sentence denotes Human colon adenocarcinoma-2 cell line (Caco2) permeability and human intestinal absorption (HIA) are key parameters to decide the total bioavailability of a drug.
T424 40012-40218 Sentence denotes All the five compounds (EGCG, TF2a, TF2b, TF3, and remdesivir) showed comparatively low Caco2 permeability potential (<8 × 10−6 cm/s) and could be absorbed via the human intestine (Larregieu & Benet, 2013).
T425 40219-40372 Sentence denotes EGCG, TF2a, TF2b, TF3, and remdesivir were predicted to be substrates of permeability glycoprotein (P-glycoprotein), which is an efflux membrane protein.
T426 40373-40555 Sentence denotes However, remdesivir was predicted as a P-glycoprotein I inhibitor, and EGCG and TF3 as a P-glycoprotein II inhibitor, whereas TF2a and TF2b as both P-glycoprotein I and II inhibitor.
T427 40556-40703 Sentence denotes Hence, above mentioned five compounds could regulate the physiological functions of P-glycoprotein (see Table S3 in the Supplementary Information).
T428 40704-40877 Sentence denotes The distribution of a drug is regulated by many parameters such as lipid-solubility, concentration in plasma and binding ability to plasma proteins, transport proteins, etc.
T429 40878-41057 Sentence denotes The volume of distribution at steady-state (VDss) suggests that EGCG, TF2a, TF2b, TF3, and remdesivir had a lower theoretical dose required for uniform distribution in the plasma.
T430 41058-41290 Sentence denotes Further, the degree of diffusion across the plasma membrane increases in the following order remdesivir < EGCG < TF2a < TF2b < TF3 (Table S4 in the Supplementary Information) as measured by the fraction that is in the unbound state.
T431 41291-41521 Sentence denotes The predictions through the distribution of the drugs via the central nervous system and blood-brain barrier suggest that these five compounds are poorly distributed to the brain and unable to penetrate the central nervous system.
T432 41522-41658 Sentence denotes However, the medium level of the lipophilicity of the drugs suggests that they would have no negative impact on nervous system exposure.
T433 41659-41729 Sentence denotes Cytochromes P450 (CYP) isozymes play crucial roles in drug metabolism.
T434 41730-41860 Sentence denotes It has been observed that TF2a, TF3, and remdesivir are a substrate of CYP3A4 and hence, can be efficiently metabolized by CYP3A4.
T435 41861-41951 Sentence denotes On the other hand, EGCG is a CYP3A4 inhibitor (Table S5 in the Supplementary Information).
T436 41952-42134 Sentence denotes On a separate note, EGCG is predominantly metabolized in the small intestine and liver by the conjugate formation of glucuronide, methyl sulfates in the urine and plasma (Chow et al.
T437 42135-42141 Sentence denotes 2005).
T438 42142-42319 Sentence denotes Among the five compounds, TF2b and TF3 were predicted as the substrate of renal organic cation transporter-2 (Renal OCT2), as shown in Table S6 in the Supplementary Information.
T439 42320-42444 Sentence denotes While EGCG, TF2a, and remdesivir are possibly cleared through other available routes such as bile, breath, faces, and sweat.
T440 42445-42543 Sentence denotes EGCG remains intact in the plasma and later excreted via bile and metabolized by colon microflora.
T441 42544-42624 Sentence denotes It is also expected that all the compounds are absorbable via oral prescription.
T442 42625-42731 Sentence denotes We have also analyzed the toxicity profiles for EGCG, TF2a, TF2b, TF3 as well as remdesivir (see Table 7).
T443 42732-42900 Sentence denotes The toxicity prediction from the AMES test (Salmonella typhimurium reverse mutation assay) exhibited that all the compounds could be considered as non-mutagenic agents.
T444 42901-42976 Sentence denotes High toxicity was observed for all the compounds in Tetrahymena pyriformis.
T445 42977-43087 Sentence denotes EGCG, TF2a, TF2b, TF3, and remdesivir were shown to inhibit the human ether-a-go-go-related gene II (hERG II).
T446 43088-43230 Sentence denotes However, Remdesivir has been shown to induce hepatotoxicity, whilst EGCG, TF2a, TF2b, TF3 are not likely to be associated with hepatotoxicity.
T447 43231-43412 Sentence denotes The maximum recommended tolerated dose (MRTD) in human prediction shows that remdesivir violate MRTD whereas natural polyphenol EGCG, TF2a, TF2b, TF3 do not fall into this category.
T448 43413-43567 Sentence denotes Remdesivir does not possess high acute toxicity whereas EGCG, TF2a, TF2b, and TF3 regarded as high acute toxic compound as it falls under minnow toxicity.
T449 43568-43655 Sentence denotes Additionally, none of the compounds predicted to be associated with skin sensitization.
T450 43656-43664 Sentence denotes Table 7.
T451 43666-43734 Sentence denotes Predicted toxicity profile of EGCG, TF3, TF2b, TF2a, and remdesivir.
T452 43735-43737 Sentence denotes S.
T453 43738-43741 Sentence denotes No.
T454 43743-43781 Sentence denotes Compounds name Toxicity prediction  
T455 43782-43816 Sentence denotes     Properties Predicted values
T456 43817-43843 Sentence denotes 1 EGCG AMES toxicity No
T457 43844-43903 Sentence denotes     Maximum tolerated dose (Human) 0.441 (log mg/kg/day)
T458 43904-43930 Sentence denotes     hERG I inhibitor No
T459 43931-43959 Sentence denotes     hERG II inhibitor Yes
T460 43960-44012 Sentence denotes     Oral rat acute toxicity (LD50) 2.522 (mol/kg)
T461 44013-44078 Sentence denotes     Oral rat chronic toxicity (LOAEL) 3.065 (log mg/kg_bw/day)
T462 44079-44103 Sentence denotes     Hepatotoxicity No
T463 44104-44130 Sentence denotes     Skin sensitivity No
T464 44131-44173 Sentence denotes     T. pyriformis toxicity 0.285 (µg/L)
T465 44174-44209 Sentence denotes     Minnow toxicity 7.713 log mM
T466 44210-44235 Sentence denotes 2 TF3 AMES toxicity No
T467 44236-44295 Sentence denotes     Maximum tolerated dose (Human) 0.438 (log mg/kg/day)
T468 44296-44322 Sentence denotes     hERG I inhibitor No
T469 44323-44351 Sentence denotes     hERG II inhibitor Yes
T470 44352-44404 Sentence denotes     Oral rat acute toxicity (LD50) 2.482 (mol/kg)
T471 44405-44470 Sentence denotes     Oral rat chronic toxicity (LOAEL) 7.443 (log mg/kg_bw/day)
T472 44471-44495 Sentence denotes     Hepatotoxicity No
T473 44496-44522 Sentence denotes     Skin sensitivity No
T474 44523-44565 Sentence denotes     T. pyriformis toxicity 0.285 (µg/L)
T475 44566-44601 Sentence denotes     Minnow toxicity 9.738 log mM
T476 44602-44628 Sentence denotes 3 TF2b AMES toxicity No
T477 44629-44688 Sentence denotes     Maximum tolerated dose (Human) 0.438 (log mg/kg/day)
T478 44689-44715 Sentence denotes     hERG I inhibitor No
T479 44716-44744 Sentence denotes     hERG II inhibitor Yes
T480 44745-44797 Sentence denotes     Oral rat acute toxicity (LD50) 2.482 (mol/kg)
T481 44798-44863 Sentence denotes     Oral rat chronic toxicity (LOAEL) 5.322 (log mg/kg_bw/day)
T482 44864-44888 Sentence denotes     Hepatotoxicity No
T483 44889-44915 Sentence denotes     Skin sensitivity No
T484 44916-44958 Sentence denotes     T. pyriformis toxicity 0.285 (µg/L)
T485 44959-44994 Sentence denotes     Minnow toxicity 8.685 log mM
T486 44995-45021 Sentence denotes 4 TF2a AMES toxicity No
T487 45022-45081 Sentence denotes     Maximum tolerated dose (Human) 0.439 (log mg/kg/day)
T488 45082-45108 Sentence denotes     hERG I inhibitor No
T489 45109-45137 Sentence denotes     hERG II inhibitor Yes
T490 45138-45190 Sentence denotes     Oral rat acute toxicity (LD50) 2.484 (mol/kg)
T491 45191-45256 Sentence denotes     Oral rat chronic toxicity (LOAEL) 5.035 (log mg/kg_bw/day)
T492 45257-45281 Sentence denotes     Hepatotoxicity No
T493 45282-45308 Sentence denotes     Skin sensitivity No
T494 45309-45351 Sentence denotes     T. pyriformis toxicity 0.285 (µg/L)
T495 45352-45387 Sentence denotes     Minnow toxicity 4.898 log mM
T496 45388-45420 Sentence denotes 5 Remdesivir AMES toxicity No
T497 45421-45479 Sentence denotes     Maximum tolerated dose (Human) 0.15 (log mg/kg/day)
T498 45480-45506 Sentence denotes     hERG I inhibitor No
T499 45507-45535 Sentence denotes     hERG II inhibitor Yes
T500 45536-45588 Sentence denotes     Oral rat acute toxicity (LD50) 2.043 (mol/kg)
T501 45589-45654 Sentence denotes     Oral rat chronic toxicity (LOAEL) 1.639 (log mg/kg_bw/day)
T502 45655-45680 Sentence denotes     Hepatotoxicity Yes
T503 45681-45707 Sentence denotes     Skin sensitivity No
T504 45708-45750 Sentence denotes     T. pyriformis toxicity 0.285 (µg/L)
T505 45751-45786 Sentence denotes     Minnow toxicity 0.291 log mM
T506 45788-45792 Sentence denotes 3.4.
T507 45794-45877 Sentence denotes Identification of target class for natural polyphenol via target prediction studies
T508 45878-46083 Sentence denotes The polyphenolic structural motif of dietary polyphenols allows them to serve as excellent hydrogen bond donors which in turn help them to strongly interact with various biomacromolecules such as proteins.
T509 46084-46214 Sentence denotes This interaction is a critical step in the regulatory role of polyphenols on various key proteins involved in cellular physiology.
T510 46215-46360 Sentence denotes The majority, if not all, of the beneficial effect of polyphenols, can be explained via the functional consequence of proteins it interacts with.
T511 46361-46460 Sentence denotes Molecular target studies help us to predict therapeutic protein targets for a given small molecule.
T512 46461-46566 Sentence denotes Herein, we analyzed the predicted interacting proteins/enzymes for EGCG, TF2a, TF2b, TF3, and remdesivir.
T513 46567-46754 Sentence denotes This study is particularly important in the current context as we think that these polyphenols could target RdRp, an important enzyme that catalyzes the RNA replication in the SARS-CoV-2.
T514 46755-46934 Sentence denotes Notably, the molecular target analysis suggests that all four polyphenols possess excellent properties of druggability, and they interact with a diverse class of proteins/enzymes.
T515 46935-47057 Sentence denotes The top 25 target classes of EGCG, TF2a, TF2b, TF3, and remdesivir are represented in the pie-chart, as shown in Figure 8.
T516 47058-47252 Sentence denotes The detailed output table with the target, common name, UniProt ID, ChEMBL ID, target class, probability, and known actives in 2D/3D are listed in Tables S7–S11 in the Supplementary Information.
T517 47253-47262 Sentence denotes Figure 8.
T518 47264-47399 Sentence denotes Molecular target predictions for (A) EGCG, (B) TF2a, (C) TF2b (D) TF3, and (E) remdesivir obtained from swiss target prediction report.
T519 47400-47474 Sentence denotes The frequency of the target classes (top 25) is depicted in the pie chart.
T520 47476-47478 Sentence denotes 4.
T521 47480-47491 Sentence denotes Conclusions
T522 47492-47803 Sentence denotes Keeping in mind that RdRp inhibitors play a crucial role to combat the SARS-CoV-2 infection, in this work, we performed a comprehensive molecular docking study with a library of hundred natural polyphenols with potential antiviral properties that may inhibit the SARS-CoV-2 RdRp and prevent the RNA replication.
T523 47804-47923 Sentence denotes We shortlisted eight natural polyphenols having binding energy −7.0 kcal/mol or less for molecular dynamics simulation.
T524 47924-48265 Sentence denotes Further, we performed 150 ns molecular dynamics simulation of RdRp/EGCG, RdRp/TF1, RdRp/TF2a, RdRp/TF2b, RdRp/TF3, RdRp/hesperidin, RdRp/myricetin, RdRp/quercetagetin, along with RdRp/remdesivir complex and computed the binding energies by the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) scheme from last 50 ns trajectories.
T525 48266-48486 Sentence denotes Our study suggests that the complex formation of the SARS-CoV-2 RdRp and eight natural polyphenols is favoured by the intermolecular van der Waals and electrostatic interactions as well as nonpolar solvation free energy.
T526 48487-48574 Sentence denotes We have also investigated the hotspot residues controlling the receptor-ligand binding.
T527 48575-48766 Sentence denotes Finally, molecular dynamics simulation and MM-PBSA study reveals that EGCG, TF2a, TF2b, and TF3 possess a better binding affinity than the control drug remdesivir against the SARS-CoV-2 RdRp.
T528 48767-48907 Sentence denotes Further, we also looked at the ADME prediction, toxicity prediction, and target analysis to assess their druggability of the five compounds.
T529 48908-49082 Sentence denotes The obtained results strongly suggest that EGCG, TF2a, TF2b, and TF3 have a stable binding affinity towards RdRp of the SARS-CoV-2 with favourable pharmacokinetic properties.
T530 49083-49156 Sentence denotes These bioactive compounds exhibit broad ranges of therapeutic properties.
T531 49157-49271 Sentence denotes Therefore, we believe that these four natural polyphenols can act as potential inhibitors for the SARS-CoV-2 RdRp.
T532 49272-49397 Sentence denotes However, further in vitro and in vivo studies need to be carried out to validate their efficacy against SARS-CoV-2 infection.
T533 49399-49421 Sentence denotes Supplementary Material
T534 49422-49443 Sentence denotes Supplemental Material
T535 49444-49480 Sentence denotes Click here for additional data file.