LitCovid-sentences  

PMC:7784829 / 1774-28504 JSONTXT 3 Projects

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Id Subject Object Predicate Lexical cue
T21 0-12 Sentence denotes Introduction
T22 13-124 Sentence denotes Coronaviruses are enveloped positive-sense single stranded RNA viruses that belong to the family coronaviridae.
T23 125-223 Sentence denotes They usually infect birds and mammals and cause mild respiratory diseases (Kahn & McIntosh, 2005).
T24 224-421 Sentence denotes However, in the recent past, these viruses have caused lethal endemics such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) endemics (Kahn & McIntosh, 2005).
T25 422-550 Sentence denotes In December 2019, Wuhan city in China became the centre of a surge in cases of pneumonia by an unknown cause (Zhu et al., 2020).
T26 551-826 Sentence denotes A novel corona virus, called SARS-CoV-2, was isolated from these pneumonia patients in January 2020 and the disease was called the Coronavirus disease 2019 (COVID-19) by the World Health Organization in February, 2020 (Gorbalenya et. al, 2020; Jiang et al., 2020; Who, 2020).
T27 827-1038 Sentence denotes Even though the epidemic may have started from a zoonotic transmission in a seafood market, that also sold wild animals, it became clear that this disease was transmitted from person to person (Li et al., 2020).
T28 1039-1275 Sentence denotes The clinical characteristics of this disease are broad, constituting asymptomatic infections, mild respiratory disease, severe pneumonia with respiratory failure and even death (Chen et al., 2020; Huang et al., 2020; Wang et al., 2020).
T29 1276-1519 Sentence denotes The COVID-19 pandemic poses a significant challenge to global public health (Phelan et al., 2020), appealing for the development of safe and successful prophylactics and therapies against infection of its causative agent, the SARS-CoV-2 virus.
T30 1520-1646 Sentence denotes SARS-CoV-2 has a genome of ∼30 kilobases, which codes for multiple structural and non-structural proteins (Chan et al., 2020).
T31 1647-1836 Sentence denotes The structural proteins, present on the surface of the mature virion, include the spike protein, the membrane protein, the envelope protein and the nucleocapsid protein (Chan et al., 2020).
T32 1837-2056 Sentence denotes The Spike protein, of the beta coronaviruses SARS-CoV-2 and SARS-CoV, enables the attachment of the virus to the cells of the lower respiratory tract of humans to gain entry into the lung tissue (Hoffmann et al., 2020).
T33 2057-2221 Sentence denotes Apart from attachment, the spike glycoprotein also appears to play a role in fusion and entry of the virus into the host (Chen et al., 2020; Hoffmann et al., 2020).
T34 2222-2406 Sentence denotes The spike protein, of the novel coronavirus, utilizes the SARS-CoV receptor, ACE2 for entry (Chen et al., 2020) and is primed by the cellular protease, TMPRSS2 (Hoffmann et al., 2020).
T35 2407-2536 Sentence denotes A serine protease inhibitor, which can act on TMPRSS2, has been shown to inhibit novel coronavirus entry (Hoffmann et al., 2020).
T36 2537-2750 Sentence denotes Therefore, the spike protein of the novel coronavirus is a good drug target and identifying small molecules that bind to S protein would inhibit viral recognition of host cells and disrupt viral-host interactions.
T37 2751-3049 Sentence denotes Curcumin, a naturally occurring phytochemical and principal component of Curcuma longa, has exhibited broad pharmacological properties including antioxidant, anti-inflammatory, anti-cancer and anti-viral effects (Khor et al., 2019; Kocaadam & Şanlier, 2017; Lal et al., 2016; Wiggers et al., 2017).
T38 3050-3186 Sentence denotes Curcumin and its derivatives, due to its rich conventional medicinal interest, has undergone comprehensive in vitro and in vivo studies.
T39 3187-3327 Sentence denotes It has, therefore, been associated with more than 100 cellular targets, including cytokines, proteins, transcription factors, and receptors.
T40 3328-3542 Sentence denotes Previous studies have shown the potential of curcumin as a treatment against Influenza A virus infection, by an effect mediated by modulating immune response to prevent injury to the lung tissue (Han et al., 2018).
T41 3543-3671 Sentence denotes Curcumin has also been shown to have anti neuraminidase (NA) activity for the influenza virus NA protein (Richart et al., 2018).
T42 3672-3840 Sentence denotes Therefore, in the present study, curcumin and its derivatives were docked onto the spike protein of the SARS-CoV and the SARS-CoV-2 to predict the binding interactions.
T43 3841-3957 Sentence denotes We found that curcumin and few of its derivatives showed promising results to be potential spike protein inhibitors.
T44 3958-4119 Sentence denotes One of the derivatives, bis-demethoxycurcumin, showed the best binding affinity to the spike protein of both the SARS-CoV and the novel corona virus, SARS-CoV-2.
T45 4120-4269 Sentence denotes The possibility for few of the curcumin derivatives, that showed good binding affinity, could be tested for further therapeutic use against COVID-19.
T46 4271-4291 Sentence denotes Experimental section
T47 4293-4310 Sentence denotes Sequence analysis
T48 4311-4423 Sentence denotes The sequences of the SARS-CoV-2 and SARS-CoV were downloaded from National Center for Biotechnology Information.
T49 4424-4592 Sentence denotes Multiple sequence analysis and pairwise sequence identity was determined using the Clustal Omega server at the European Bioinformatics Institute (Sievers et al., 2011).
T50 4594-4624 Sentence denotes Preparation of coordinate file
T51 4625-4706 Sentence denotes The X-ray crystal structure of spike surface glycoprotein of SARS-CoV (PDB entry:
T52 4707-4816 Sentence denotes 6CRV, resolution = 3.2 Å) and co-crystallized structure of SARS-CoV-2 RBD with human ACE2 Protein (PDB entry:
T53 4817-4907 Sentence denotes 6M0J, resolution = 2.45 Å) was retrieved from Protein Data Bank (https:/www.rscb.org/pdb).
T54 4908-5272 Sentence denotes The protein structure was prepared using the Discovery Studio Visualizer (version 3.1) and AutoDock Tools (ADT; version 1.5.4) through different steps viz. removal of water molecules and co-crystallized ligand, addition of missing hydrogen atoms, addition of Gasteiger-Marsili and Kollman charges, merging of non-polar hydrogens, and assignment of rotatable bonds.
T55 5273-5339 Sentence denotes The file was then saved in pdbqt file format for further analysis.
T56 5341-5363 Sentence denotes Preparation of ligands
T57 5364-5497 Sentence denotes The chemical structures of curcumin derivatives were constructed using Chem3D 15.0 module of ChemOffice 15.0 and saved in PDB format.
T58 5498-5667 Sentence denotes The structures were optimized using “Prepare Ligands” in the AutoDock 4.2, flexible torsions were assigned and the acyclic dihedral angles were allowed to rotate freely.
T59 5668-5734 Sentence denotes The file was then saved as pdbqt file format for further analysis.
T60 5736-5753 Sentence denotes Molecular docking
T61 5754-5935 Sentence denotes Molecular docking simulations were conducted on the curcumin derivatives using the AutoDock 4.2 to get insight into their binding preferences within the active site of the receptor.
T62 5936-6057 Sentence denotes The molecular docking simulations were performed on the PC based machines running on Windows 7 (x86) as operating system.
T63 6058-6255 Sentence denotes The software included MGL tools 1.5.4 based AutoDock 4.2 (www.scripps.edu) which uses Python 2.7 language - Cygwin C:\program (www.cygwin.com) and Python 2.5 (www.python.com) (Morris et al., 2009).
T64 6257-6276 Sentence denotes Docking methodology
T65 6277-6399 Sentence denotes The flexible docking was performed using the refined spike protein of SARS-CoV (6CRV) and RBD domain of SARS-CoV-2 (6M0J).
T66 6400-6503 Sentence denotes The grid maps of the interaction energies of various atom types were pre-calculated using AutoGrid 4.2.
T67 6504-6704 Sentence denotes In each docking for spike surface glycoprotein and spike RBD, a grid box was created using a grid map of 45 × 45 × 45 points, 60 × 60 × 60 points with grid spacing of 0.375 Å and 0.420 Å respectively.
T68 6705-6802 Sentence denotes The grid maps were centred on the corresponding ligand binding site within the protein structure.
T69 6803-6925 Sentence denotes Lamarckian Genetic Algorithm (LGA) was adopted to perform docking simulations using the following default parameters, viz.
T70 6926-7283 Sentence denotes 100 independent runs with step sizes of 0.2 Å for translations and 5 Å for orientations and torsions, an initial population of random individuals with a population size of 150 individuals, a maximum of 2.5 × 106 energy evaluations, maximum number of generations of 27,000; mutation and crossover rates of 0.02 and 0.8 respectively and an elitism value of 1.
T71 7284-7449 Sentence denotes All the computations were carried out on Cygwin and was used to generate both grid parameter file (.gpf file) and docking parameter file (.dpf file) for each ligand.
T72 7450-7605 Sentence denotes The docked conformations of each ligand were ranked into clusters based on the binding energy and the top ranked conformations were used for further study.
T73 7606-7733 Sentence denotes The pose with the lowest ΔG-score was considered the best fitted one and was further analyzed for Ligand-receptor interactions.
T74 7735-7798 Sentence denotes In-silico drug-likeness and pharmacokinetic property prediction
T75 7799-8018 Sentence denotes The in-silico prediction studies were performed, using pkCSM online prediction platforms (Pires et al., 2015), to assess the theoretical pharmacokinetic parameters of the ligands to predict the drug-likeness of ligands.
T76 8019-8207 Sentence denotes The software calculated pharmaceutically relevant properties such as H-bond donor, H-bond acceptor, octanol-water partition coefficient (LogP), surface area, and number of rotatable bonds.
T77 8208-8638 Sentence denotes In addition the ADME parameters of the curcumin analogs such as water solubility, Caco2 permeability, human intestinal absorption, skin permeability, P-glycoprotein I and II inhibition, volume of distribution, fraction of unbound drug, Blood Brain Barrier and CNS permeability, cytochrome P450 (CYP3A4 and CYP2C9 inhibition) inhibition, total clearance, action as renal OCT2 (organic cation transporter 2) substrate were analysed.
T78 8640-8647 Sentence denotes Results
T79 8649-8722 Sentence denotes Sequence alignment of the SARS-CoV-2 and SARS-CoV spike protein sequences
T80 8723-8931 Sentence denotes Prior to performing the docking studies the multiple sequence alignment was carried out for the spike proteins of the novel corona virus, SARS-CoV-2 and the 2002 SARS-CoV (Supplementary Figure 1 and Table 1).
T81 8932-9085 Sentence denotes These results show that there is a very high percentage identity (greater than 99%) among the spike protein of the novel corona virus SARS-CoV-2 strains.
T82 9086-9172 Sentence denotes There was around 74% identity of the SARS-CoV-2 spike proteins with the 2002 SARS-CoV.
T83 9173-9325 Sentence denotes Therefore, the SARS-CoV-2 spike protein is very much closer to SARS-CoV than to the other corona viruses as shown in other studies (Ahmed et al., 2020).
T84 9326-9335 Sentence denotes Figure 1.
T85 9337-9451 Sentence denotes The curcumin and its derivatives which displayed high binding affinity for SARS-CoV-2 and SARS-CoV spike proteins.
T86 9452-9460 Sentence denotes Table 1.
T87 9462-9538 Sentence denotes Percentage identity Matrix of Spike glycoprotein of SARS-CoV-2 and SARS-CoV.
T88 9539-9763 Sentence denotes Indian 1 and 2 (QHS34546.1 and QIA98583.1), Korea (QHZ00379.1), Brazil (QIG55994.1), USA (QHO60594.1), Wuhan (QHD43416.1), Pakistan (QIQ22760.1), Italy (QIA98554.1), Australia (QHR84449.1) are spike proteins from SARS-CoV-2.
T89 9764-9839 Sentence denotes SARS-6CRV is the spike protein from the 2002 SARS-CoV spike protein (6CRV).
T90 9840-9935 Sentence denotes Viral Strain SARS-CoV Indian1 Korea Indian2 Brazil USA Wuhan Pakistan Italy Australia
T91 9936-10012 Sentence denotes SARS-CoV 100 73.75 73.77 73.69 73.77 73.77 73.77 73.77 73.77 73.77
T92 10013-10088 Sentence denotes Indian1 73.75 100 99.84 99.84 99.92 99.92 99.92 99.92 99.92 99.84
T93 10089-10162 Sentence denotes Korea 73.77 99.84 100 99.84 99.92 99.92 99.92 99.92 99.92 99.84
T94 10163-10238 Sentence denotes Indian2 73.69 99.84 99.84 100 99.92 99.92 99.92 99.92 99.92 99.84
T95 10239-10305 Sentence denotes Brazil 73.77 99.92 99.92 99.92 100 100 100 100 100 99.92
T96 10306-10369 Sentence denotes USA 73.77 99.92 99.92 99.92 100 100 100 100 100 99.92
T97 10370-10435 Sentence denotes Wuhan 73.77 99.92 99.92 99.92 100 100 100 100 100 99.92
T98 10436-10504 Sentence denotes Pakistan 73.77 99.92 99.92 99.92 100 100 100 100 100 99.92
T99 10505-10570 Sentence denotes Italy 73.77 99.92 99.92 99.92 100 100 100 100 100 99.92
T100 10571-10648 Sentence denotes Australia 73.77 99.84 99.84 99.84 99.92 99.92 99.92 99.92 99.92 100
T101 10650-10675 Sentence denotes Molecular docking studies
T102 10676-10787 Sentence denotes The three-dimensional structure of the SARS-CoV spike protein and SARS-CoV-2 Spike protein RBD has been solved.
T103 10788-10927 Sentence denotes The PDB files of the SARS-CoV spike protein (6CRV) and the Spike protein RBD of the SARS-CoV-2 (6M0J) was downloaded from the PDB databank.
T104 10928-11073 Sentence denotes These structures were used to predict the ability of the binding of curcumin and its derivatives to the spike proteins of the two corona viruses.
T105 11074-11179 Sentence denotes Curcumin and 24 of its derivatives (Figure 1 and Supplementary Figure 2) were docked on to 6CRV and 6M0J.
T106 11180-11398 Sentence denotes Tables 2 and 3 gives the binding energies of curcumin and its derivatives with 6CRV (binding energies ranged from −10.98 to −5.12 kcal/mol) and with 6M0J (binding energies ranged −10.01 to −5.33 kcal/mol) respectively.
T107 11399-11784 Sentence denotes Visual examination of the computationally docked optimal binding poses of curcumin and its derivatives on 6CRV and 6MOJ revealed the important role of various types of interactions viz. hydrogen bonding and hydrophobic interactions, including π–π stacking, π–cation, and π–σ interactions in the stability of the binding of the curcumin/derivatives to the spike protein (6CRV and 6M0J).
T108 11785-11865 Sentence denotes All compounds showed one or more hydrogen bonds with 6CRV and 6M0J except a few.
T109 11866-11875 Sentence denotes Figure 2.
T110 11877-12336 Sentence denotes Molecular docking of Bis-demethoxy curcumin on SARS-CoV spike protein (6CRV). (A) 3 D structure of SARS-CoV Spike Glycoprotein Macromolecule (6CRV). (B) Binding Interaction of Bis-demethoxy curcumin with amino acid residues of SARS-CoV Spike glycoprotein (PDB ID-6CRV). (C) Superimposed binding mode of Bis-demethoxy curcumin with SARS-CoV Spike protein. (D) 2 D representation of the binding interaction of Bis-demethoxy curcumin with SARS-CoV Spike protein.
T111 12337-12345 Sentence denotes Table 2.
T112 12347-12440 Sentence denotes Molecular docking results of curcumin and its derivatives with SARS-CoV Spike protein (6CRV).
T113 12441-12507 Sentence denotes The top hits with the binding energy lesser than -8.4 are in bold.
T114 12508-12589 Sentence denotes Compound Binding Energy (ΔG) Ligand Efficiency Intermolecular energy XPH-Bond
T115 12590-12633 Sentence denotes Curcumin –10.1 –0.14 –8.24 –10.9724
T116 12634-12669 Sentence denotes BHBC –8.28 –0.13 –7.87 –3.42239
T117 12670-12704 Sentence denotes MNC –8.01 –0.43 –6.98 –8.01452
T118 12705-12745 Sentence denotes BDMC –10.98 –0.18 –8.94 –14.0467
T119 12746-12771 Sentence denotes 1 –5.12 –0.25 –4.17 0
T120 12772-12808 Sentence denotes 2 –8.55 –0.41 –6.56 –18.4317
T121 12809-12841 Sentence denotes 3 –6.56 –0.21 –4.92 –11.1148
T122 12842-12878 Sentence denotes 4 –8.69 –0.13 –6.94 –19.1539
T123 12879-12911 Sentence denotes 5 –7.03 –0.19 –5.93 –8.47153
T124 12912-12944 Sentence denotes 6 –6.59 –0.36 –5.12 –7.41531
T125 12945-12977 Sentence denotes 7 –7.96 –0.21 –6.14 –7.98548
T126 12978-13010 Sentence denotes 8 –7.55 –0.19 –5.14 –6.14537
T127 13011-13036 Sentence denotes 9 –6.91 –0.21 –5.18 0
T128 13037-13070 Sentence denotes 10 –7.75 –0.21 –6.14 –6.73473
T129 13071-13104 Sentence denotes 11 –8.02 –0.19 –6.19 –17.2465
T130 13105-13138 Sentence denotes 12 –7.85 –0.38 –6.25 –14.6321
T131 13139-13172 Sentence denotes 13 –5.94 –0.29 –4.12 –11.3576
T132 13173-13210 Sentence denotes 14 –8.75 –0.25 –7.19 –21.1412
T133 13211-13245 Sentence denotes 15 –7.87 –0.38 –7.26 –0.473228
T134 13246-13284 Sentence denotes 16 –8.47 –0.25 –6.88 –8.458912
T135 13285-13320 Sentence denotes DMC –7.89 –0.21 –6.41 –10.47057
T136 13321-13355 Sentence denotes FAC –7.17 –0.36 –5.15 –9.14873
T137 13356-13390 Sentence denotes IBC –7.91 –0.23 –7.17 –6.90341
T138 13391-13425 Sentence denotes IVC –7.43 –0.44 –6.67 –19.9864
T139 13426-13460 Sentence denotes SYC –6.82 –0.26 –5.45 –9.44678
T140 13461-13481 Sentence denotes Abbreviations: BHBC:
T141 13482-13536 Sentence denotes 3-5-di-tert-butyl-4-hydroxybenzaldehyde curcumin, MNC:
T142 13537-13579 Sentence denotes 4-methoxy-1-naphthaldehyde curcumin, BDMC:
T143 13580-13608 Sentence denotes Bis-demethoxy curcumin, DMC:
T144 13609-13633 Sentence denotes Demethoxy curcumin, FAC:
T145 13634-13661 Sentence denotes Ferulic-acid curcumin, IBC:
T146 13662-13686 Sentence denotes Ibuprofen curcumin, IVC:
T147 13687-13713 Sentence denotes Isovanillin curcumin, SYC:
T148 13714-13738 Sentence denotes Syringaldehyde curcumin.
T149 13739-13747 Sentence denotes Table 3.
T150 13749-13869 Sentence denotes Molecular docking analysis of curcumin and its derivatives with SARS-CoV-2 Spike protein Receptor binding domain (6M0J).
T151 13870-13936 Sentence denotes The top hits with the binding energy lesser than -8.4 are in bold.
T152 13937-14018 Sentence denotes Compound Binding Energy (ΔG) Ligand Efficiency Intermolecular energy XPH-Bond
T153 14019-14062 Sentence denotes Curcumin –9.81 –0.15 –8.35 –15.1512
T154 14063-14091 Sentence denotes BHBC −5.33 –0.13 –7.96 0
T155 14092-14126 Sentence denotes MNC –7.96 –0.27 –7.38 –4.24687
T156 14127-14167 Sentence denotes BDMC –10.01 –0.12 –9.18 –13.9824
T157 14168-14200 Sentence denotes 1 –7.58 –0.36 –6.19 –18.3489
T158 14201-14235 Sentence denotes 2 –8.81 –0.31 –8.38 1.2654
T159 14236-14268 Sentence denotes 3 –6.14 –0.34 –5.45 –6.95102
T160 14269-14305 Sentence denotes 4 –8.88 –0.18 –7.98 –14.0321
T161 14306-14337 Sentence denotes 5 –6.23 –0.26 –5.88 –3.5891
T162 14338-14370 Sentence denotes 6 –7.16 –0.37 –6.15 –10.1688
T163 14371-14403 Sentence denotes 7 –6.89 –0.25 –5.98 –9.12515
T164 14404-14436 Sentence denotes 8 –5.49 –0.12 –3.90 –5.92265
T165 14437-14469 Sentence denotes 9 –6.92 –0.18 –6.22 –6.96719
T166 14470-14499 Sentence denotes 10 –7.03 –0.24 –6.33 –7.0
T167 14500-14533 Sentence denotes 11 –6.88 –0.27 –6.23 –6.44363
T168 14534-14566 Sentence denotes 12 –7.95 –0.41 –5.70 –2.5581
T169 14567-14600 Sentence denotes 13 –6.11 –0.39 –5.42 –7.34943
T170 14601-14634 Sentence denotes 14 –7.45 –0.19 –6.40 –10.5367
T171 14635-14668 Sentence denotes 15 –5.74 –0.39 –5.51 –2.36748
T172 14669-14702 Sentence denotes 16 –7.83 –0.27 –7.48 –6.64321
T173 14703-14737 Sentence denotes DMC –5.98 –0.19 –5.38 –5.99913
T174 14738-14772 Sentence denotes FAC –5.85 –0.38 –5.25 –6.46613
T175 14773-14807 Sentence denotes IBC –6.65 –0.15 –6.20 –1.52841
T176 14808-14846 Sentence denotes IVC –8.96 –0.43 –7.73 –12.2707
T177 14847-14880 Sentence denotes SYC –5.87 –0.29 –5.43 –4.4411
T178 14881-14901 Sentence denotes Abbreviations: BHBC:
T179 14902-14956 Sentence denotes 3-5-di-tert-butyl-4-hydroxybenzaldehyde curcumin, MNC:
T180 14957-14999 Sentence denotes 4-methoxy-1-naphthaldehyde curcumin, BDMC:
T181 15000-15028 Sentence denotes Bis-demethoxy curcumin, DMC:
T182 15029-15053 Sentence denotes Demethoxy curcumin, FAC:
T183 15054-15081 Sentence denotes Ferulic-acid curcumin, IBC:
T184 15082-15106 Sentence denotes Ibuprofen curcumin, IVC:
T185 15107-15133 Sentence denotes Isovanillin curcumin, SYC:
T186 15134-15158 Sentence denotes Syringaldehyde curcumin.
T187 15159-15448 Sentence denotes In 6CRV, it was found that ARG99, GLY100, TRP 101, ILE116, ILE117, ASN118, VAL123, MET144, SER165, ASP166, PHE168, ARG183, PHE185, LYS198, ILE219, PHE220 were the major amino acids involved in hydrogen bonding, hydrophobic and van der Waals interaction with most of the curcumin compounds.
T188 15449-15571 Sentence denotes However, majority of the curcumin compounds exhibited hydrogen bonding with ARG99, MET144, LYS198 except compound 1 and 9.
T189 15572-15815 Sentence denotes In addition, all the compounds exhibited hydrophobic (π–π stacking, π–cation, and π–σ) interactions with ASP166, VAL123, PHE185 and van der Waals interaction with GLY100, TRP 101, ILE117, ASN118, ARG183, ILE116, PHE168, SER165, PHE220, ILE219.
T190 15816-15975 Sentence denotes All compounds showed one or more hydrogen bonding interactions with spike RBD of the SARS-CoV-2 (6M0J) except 3-5-di-tert-butyl-4-hydroxybenzaldehyde curcumin.
T191 15976-16226 Sentence denotes It was found that ARG355, TYR396, PRO426, ASP428, THR430, GLY431, PHE429, PHE 464, GLU516, SER514, LEU517 and PHE515 were the major amino acids involved in hydrogen bonding hydrophobic and van der Waals interaction with the all of curcumin compounds.
T192 16227-16327 Sentence denotes However, majority of the curcumin compounds exhibit hydrogen bonding with ARG355, LEU517 and THR430.
T193 16328-16521 Sentence denotes In addition, the compounds exhibited hydrophobic (π–π stacking, π–cation, and π–σ) and van der Waals interactions with PHE464, GLY431, GLU516, SER514, PHE515, TYR396, PRO426, ASP428 and PHE429.
T194 16522-16672 Sentence denotes The curcumin derivative with the best binding affinity was Bis-demethoxycurcumin for both 6CRV (ΔG = −10.98 kcal/mol) and 6M0J (ΔG = −10.01 kcal/mol).
T195 16673-16789 Sentence denotes The native compound, curcumin, demonstrated a binding energy of −9.81 kcal/mol for 6M0J and −10.1 kcal/mol for 6CRV.
T196 16790-16930 Sentence denotes Binding mode of Bis-demethoxycurcumin with SARS-CoV Spike protein and SARS-CoV-2 Spike protein RBD is shown in Figure 2 and 3, respectively.
T197 16931-16940 Sentence denotes Figure 3.
T198 16942-17458 Sentence denotes Molecular docking of Bis-demethoxy curcumin on SARS-CoV-2 spike protein receptor binding domain (6M0J). (A) 3D structure of SARS-CoV-2 spike protein RBD bound with ACE2 protein Macromolecule. (B) Binding Interaction of Bis-demethoxy curcumin with amino acid residue of spike protein RBD of SARS-CoV-2 (PDB ID-6M0J). (C) Superimposed binding mode of Bis-demethoxy curcumin, docked with SARS-CoV-2 spike protein RBD. (D) 2D representation of the binding interaction of Bis-demethoxy curcumin with SARS-CoV-2 spike RBD.
T199 17460-17523 Sentence denotes In-silico drug-likeness and pharmacokinetic property prediction
T200 17524-17661 Sentence denotes All the structures used for docking were analysed for in silico drug-likeness based on the Lipinski’s rules using pkCSM server (Table 4).
T201 17662-17818 Sentence denotes The lipophilicity (expressed as LogP) predicted for all the compounds were found to be well above the traditionally cut-off value of 5 used for drug design.
T202 17819-17972 Sentence denotes Curcumin and its derivatives, used in this study, show suitable MW values (MW < 500) essential for a successful penetration through biological membranes.
T203 17973-18099 Sentence denotes The surface area (SA) for all the compounds was observed to be in the range 115.89 − 240.65 Å2 which is well within the limit.
T204 18100-18357 Sentence denotes All compounds, except 5-di-tert-butyl-4-hydroxybenzaldehyde curcumin (BHBC), 4-methoxy-1-naphthaldehyde curcumin (MNC), Syringaldehyde curcumin (SYC) and compound-16, fall into the appropriate range indicating good bioavailability of the candidate molecule.
T205 18358-18502 Sentence denotes The number of hydrogen bond acceptors (HBA, ≤10) and donors (HBD, ≤5) for all the compounds were in accordance with the Lipinski’s rule of five.
T206 18503-18511 Sentence denotes Table 4.
T207 18513-18579 Sentence denotes In-silico prediction of drug-likeness for curcumin derivatives[a].
T208 18580-18642 Sentence denotes Compound MW LogP SA HBA HBD nviolations Rotatable bonds
T209 18643-18680 Sentence denotes BHBC 534.78 8.93 236.0 4 3 1 6
T210 18681-18719 Sentence denotes MNC 538.59 6.14 232.11 7 2 1 11
T211 18720-18758 Sentence denotes BDMC 308.33 3.83 133.51 4 3   5
T212 18759-18795 Sentence denotes 1 270.353 4.21 115.89 3 1   4
T213 18796-18832 Sentence denotes 2 332.739 3.79 136.57 5 4   4
T214 18833-18869 Sentence denotes 3 314.337 3.77 133.64 5 4   4
T215 18870-18905 Sentence denotes 4 322.36 4.36 139.56 3 3   4
T216 18906-18942 Sentence denotes 5 364.441 4.93 159.62 4 0   5
T217 18943-18979 Sentence denotes 6 320.388 4.95 141.45 4 3   1
T218 18980-19015 Sentence denotes 7 325.32 3.60 138.02 5 1   6
T219 19016-19052 Sentence denotes 8 329.193 4.45 125.75 2 1   4
T220 19053-19089 Sentence denotes 9 462.181 5.24 164.71 7 2   0
T221 19090-19127 Sentence denotes 10 351.358 4.13 149.74 4 5   1
T222 19128-19165 Sentence denotes 11 360.375 5.07 149.89 2 1   3
T223 19166-19203 Sentence denotes 12 419.565 6.24 185.40 9 4   1
T224 19204-19241 Sentence denotes 13 389.495 5.22 171.67 4 4   1
T225 19242-19279 Sentence denotes 14 342.778 3.81 143.82 4 2   2
T226 19280-19317 Sentence denotes 15 469.629 4.38 208.20 6 5   1
T227 19318-19356 Sentence denotes 16 486.564 6.19 211.58 11 6 1 0
T228 19357-19395 Sentence denotes DMC 342.391 3.20 146.43 5 2   9
T229 19396-19434 Sentence denotes FAC 550.604 4.7 232.81 9 2   15
T230 19435-19474 Sentence denotes IBC 556.655 5.24 240.62 7 1   15
T231 19475-19514 Sentence denotes IVC 504.535 4.69 214.22 8 3   11
T232 19515-19554 Sentence denotes SYC 430.453 3.77 180.12 10 8 1 3
T233 19555-19770 Sentence denotes [a]  MW = Molecular weight, LogP = octanol-water partition coefficient, SA = Surface Area, HBA = Number of hydrogen bond acceptor, HBD = Number of hydrogen bond donor, nviolations = violations from Lipinski’s rule.
T234 19771-19776 Sentence denotes BHBC:
T235 19777-19831 Sentence denotes 3-5-di-tert-butyl-4-hydroxybenzaldehyde curcumin, MNC:
T236 19832-19874 Sentence denotes 4-methoxy-1-naphthaldehyde curcumin, BDMC:
T237 19875-19903 Sentence denotes Bis-demethoxy curcumin, DMC:
T238 19904-19928 Sentence denotes Demethoxy curcumin, FAC:
T239 19929-19956 Sentence denotes Ferulic-acid curcumin, IBC:
T240 19957-19981 Sentence denotes Ibuprofen curcumin, IVC:
T241 19982-20008 Sentence denotes Isovanillin curcumin, SYC:
T242 20009-20033 Sentence denotes Syringaldehyde curcumin.
T243 20034-20189 Sentence denotes Additionally, a variety of key ADMET (Absorption, Distribution, Metabolism and Excretion) properties have also been calculated with the aid of pkCSMserver.
T244 20190-20224 Sentence denotes The results are listed in Table 5.
T245 20225-20527 Sentence denotes All curcumin derivatives showed moderate to high water solubility ranging from −2.91 log mol/L (BHBC) to −6.99 log mol/L (compound-12), in addition to high Caco-2 permeability (permeation > 0.90) except compound BHBC and MNC (permeation = 0.67 and 0.43 respectively) which showed moderate permeability.
T246 20528-20651 Sentence denotes Intestinal absorption (IA) has been found to be greater than 85% indicating good permeation across the intestinal membrane.
T247 20652-20740 Sentence denotes Further, all curcumin compounds showed good permeation through skin (permeation > −2.5).
T248 20741-20975 Sentence denotes Additionally, all curcumin compounds showed no inhibition towards P-glycoprotein I and P-glycoprotein II, except compounds BHBC, MNC, compound-13 and Ferrulic acid curcumin (FAC) which demonstrated inhibition towards P-glycoprotein I.
T249 20976-21113 Sentence denotes Furthermore, all curcumin compounds showed poor BBB permeability and moderate CNS permeability except Isovanillin curcumin (IVC) and SYC.
T250 21114-21287 Sentence denotes All showed inhibition towards the metabolizing enzyme CYP3A4 except BHBC, compounds-8, -11, -14, -15 and -16, while except compound-15, all showed inhibition towards CYP2C9.
T251 21288-21440 Sentence denotes All curcumin derivatives were found to show the total clearance in the range 0.10 log mL/min/kg (compound-1 and -4) to 1.01 log mL/min/kg (compound-15).
T252 21441-21649 Sentence denotes Further, all curcumin derivatives except compound 15 were found to act as OCT2 substrate, thus indicating that these compounds will not have any adverse interactions and no negative effect on renal clearance.
T253 21650-21658 Sentence denotes Table 5.
T254 21660-21714 Sentence denotes In-silico ADME prediction for curcumin derivatives[a].
T255 21715-21768 Sentence denotes Comp Absorption Distribution Metabolism Excretion
T256 21769-21836 Sentence denotes   WS CP IA SP PI-1 PI-2 VD FU BBB CNS CI-1 CI-2 TC RS
T257 21837-21924 Sentence denotes BHBC –2.91 0.67 88.62 –2.73 Yes Yes –0.39 0.31 –0.67 –0.85 No Yes 0.15 No
T258 21925-22010 Sentence denotes MNC –3.64 0.43 100 –2.73 Yes Yes –1.45 0.33 –0.39 –2.73 Yes Yes 0.26 No
T259 22011-22097 Sentence denotes BDMC –4.43 1.01 95.92 –2.99 No No –0.22 0.08 –0.72 –2.11 Yes Yes 0.12 No
T260 22098-22179 Sentence denotes 1 –4.66 1.25 91.80 –2.51 No No 0.18 0.06 0.01 –1.45 Yes Yes 0.10 No
T261 22180-22263 Sentence denotes 2 –3.23 0.93 89.16 –2.76 No No –0.07 0.12 –1.07 –2.29 Yes Yes 0.05 No
T262 22264-22347 Sentence denotes 3 –3.19 0.94 89.70 –2.76 No No –0.02 0.13 –1.06 –2.27 Yes Yes 0.06 No
T263 22348-22427 Sentence denotes 4 –4.11 0.92 87.64 –3.07 No No 0.09 0 –0.74 –1.85 Yes Yes 0.10 No
T264 22428-22507 Sentence denotes 5 –6.39 1.06 94.85 –2.49 No No 0.25 0 –0.03 –1.30 Yes Yes 0.22 No
T265 22508-22587 Sentence denotes 6 –5.42 1.43 90.49 –2.73 No No 0.05 0 –0.33 –1.29 Yes Yes 0.23 No
T266 22588-22667 Sentence denotes 7 –4.54 1.04 91.97 –2.73 No No –0.37 0 0.28 –2.20 Yes Yes 0.13 No
T267 22668-22745 Sentence denotes 8 –5.09 1.66 90.44 –2.29 No No 0.27 0 0.16 –1.47 No Yes 0.14 No
T268 22746-22824 Sentence denotes 9 –7.03 1.13 93.34 –2.51 No No 0.37 0 0.46 –1.26 Yes Yes 0.26 No
T269 22825-22906 Sentence denotes 10 –4.89 0.94 91.50 –2.74 No No –0.04 0 –0.24 –1.93 Yes Yes 0.11 No
T270 22907-22985 Sentence denotes 11 –5.93 1.28 89.16 –2.59 No No 0.36 0 0.66 –1.40 No Yes 0.13 No
T271 22986-23066 Sentence denotes 12 –6.99 1.02 91.30 –2.75 No No 0.66 0 –0.32 –1.85 Yes Yes 1.04 No
T272 23067-23149 Sentence denotes 13 –5.42 1.27 92.76 –2.80 Yes Yes 0.54 0 –0.02 –1.58 Yes Yes 0.26 No
T273 23150-23233 Sentence denotes 14 –4.20 1.12 90.31 –2.92 No No –0.04 0.01 –0.31 –1.33 No Yes 0.08 No
T274 23234-23316 Sentence denotes 15 –3.76 0.97 88.86 –2.79 No No 1.90 0.16 –0.20 –1.26 No No 1.01 Yes
T275 23317-23400 Sentence denotes 16 –6.92 0.90 94.67 –2.73 No No –0.59 0.07 –0.72 –2.62 No Yes 0.41 No
T276 23401-23486 Sentence denotes DMC –3.95 0.99 92.03 –2.74 No No –0.06 0.12 –0.23 –2.66 Yes Yes 0.32 No
T277 23487-23574 Sentence denotes FAC –4.02 1.41 83.68 –2.76 Yes Yes –0.58 0.24 –0.91 –3.26 Yes Yes 0.55 No
T278 23575-23660 Sentence denotes IBC –4.36 0.91 91.72 –2.73 No No –0.88 0.18 –0.53 –2.77 Yes Yes 0.62 No
T279 23661-23746 Sentence denotes IVC –3.95 0.96 89.31 –2.73 No No –0.60 0.24 –1.37 –3.02 Yes Yes 0.16 No
T280 23747-23831 Sentence denotes SYC –3.89 1.01 89.15 –2.73 No No 0.28 0.17 –1.47 –3.14 Yes Yes 0.23 No
T281 23832-24349 Sentence denotes [a]  Abbreviations: WS—Water solubility (log mol/L), CP—Caco2 permeability (log Papp in 10-6 cm/s), IA—Human intestinal absorption (% Absorbed), SP—Skin permeability (log Kp),PI-1—P-glycoprotein I inhibitor, PI-2—P-glycoprotein II inhibitor, VD—Human volume ofdistribution (log L/kg), FU—Fraction unbound (human) (Fu), BBB—BBB permeability (logBB), CNS—CNS permeability (log PS), CI-1—CYP3A4 inhibitor, CI-2—CYP2C9 inhibitor,TC—Total clearance (log mL/min/kg), RS—Renal OCT2 (organic cation transporter 2) substrate.
T282 24350-24355 Sentence denotes BHBC:
T283 24356-24410 Sentence denotes 3-5-di-tert-butyl-4-hydroxybenzaldehyde curcumin, MNC:
T284 24411-24453 Sentence denotes 4-methoxy-1-naphthaldehyde curcumin, BDMC:
T285 24454-24482 Sentence denotes Bis-demethoxy curcumin, DMC:
T286 24483-24507 Sentence denotes Demethoxy curcumin, FAC:
T287 24508-24535 Sentence denotes Ferulic-acid curcumin, IBC:
T288 24536-24560 Sentence denotes Ibuprofen curcumin, IVC:
T289 24561-24587 Sentence denotes Isovanillin curcumin, SYC:
T290 24588-24612 Sentence denotes Syringaldehyde curcumin.
T291 24614-24639 Sentence denotes Conclusion and discussion
T292 24640-24736 Sentence denotes The spike proteins of corona viruses are essential for entry of the virus into the target cells.
T293 24737-24905 Sentence denotes The spike protein exists as a trimer on the surface of the virus with one of the monomer in up conformation and the other two in down conformation (Wrapp et al., 2020).
T294 24906-25047 Sentence denotes The N-terminal region (S1) of the S protein is important for binding to the cellular receptor ACE2 (Hoffmann et al., 2020; Tai et al., 2020).
T295 25048-25224 Sentence denotes The S protein undergoes priming by cellular protease, TMPRSS2 and the S2 region of the protein is responsible for fusion of viral and cellular membrane (Hoffmann et al., 2020).
T296 25225-25384 Sentence denotes Therefore, identifying therapeutics for the S protein of the novel corona virus could potentially target the critical process of entry and fusion of the virus.
T297 25385-25500 Sentence denotes Curcumin and its derivatives are known for their many biological activities, one of them is its antiviral activity.
T298 25501-25631 Sentence denotes Therefore, here, we examined the potential of curcumin, and its derivatives, to bind to the SARS-CoV and SARS-CoV-2 spike protein.
T299 25632-25981 Sentence denotes From our computational molecular docking approach (using auto dock 4.2, PDB ID - 6CRV, 6M0J) and in-silico ADMET tool, we predicted that Bis-demethoxy curcumin, compound-4 and compound-2 were the most recommended curcumin compounds which bind to RBD domain of the SARS-CoV-2 Spike protein and SARS-CoV spike protein efficiently in in silico studies.
T300 25982-26211 Sentence denotes Curcumin has earlier shown to have specific inhibitory effect on the NA activity in influenza virus (Chen et al., 2013; Richart et al., 2018) and modulating immune response to prevent injury to the lung tissue (Han et al., 2018).
T301 26212-26360 Sentence denotes Till date, Bis-demethoxy curcumin has shown to have anti-cancer and hepato-protective activities (Kumaravel et al., 2013; Rajagopalan et al., 2010).
T302 26361-26441 Sentence denotes This is the first time; it is predicted to have a potential anti-viral activity.
T303 26442-26644 Sentence denotes Therefore, these curcumin derivatives, which have been predicted to bind to the SARS-CoV-2 spike protein, could be explored as probable inhibitors of COVID-19 spike protein through experimental studies.
T304 26646-26668 Sentence denotes Supplementary Material
T305 26669-26693 Sentence denotes Supplementary_Figure.pdf
T306 26694-26730 Sentence denotes Click here for additional data file.