> top > docs > PMC:7784834 > spans > 9485-17959 > annotations

PMC:7784834 / 9485-17959 JSONTXT

Annnotations TAB JSON ListView MergeView

LitCovid-PubTator

Id Subject Object Predicate Lexical cue tao:has_database_id
179 81-86 Gene denotes spike Gene:43740568
180 134-144 Species denotes SARS-CoV-2 Tax:2697049
181 349-352 Species denotes SAR Tax:2698737
182 353-358 Species denotes CoV-2 Tax:2697049
183 359-364 Gene denotes spike Gene:43740568
184 778-786 Chemical denotes hydrogen MESH:D006859
185 860-869 Chemical denotes disulfide MESH:D004220
186 893-898 Chemical denotes water MESH:D014867
187 188-196 Disease denotes COVID-19 MESH:C000657245
188 197-206 Disease denotes infection MESH:D007239
189 430-433 CellLine denotes LU7 CVCL:M631
191 2012-2017 Gene denotes spike Gene:43740568
196 2819-2824 Gene denotes spike Gene:43740568
197 2854-2857 Species denotes SAR Tax:2698737
198 2858-2863 Species denotes CoV-2 Tax:2697049
199 3546-3566 Disease denotes SARS-CoV-2 infection MESH:C000657245
209 3665-3670 Gene denotes spike Gene:43740568
210 4219-4224 Gene denotes spike Gene:43740568
211 4822-4827 Gene denotes spike Gene:43740568
212 4309-4327 Gene denotes –6, –4, –6, and –4
213 3654-3664 Species denotes SARS-CoV-2 Tax:2697049
214 3918-3923 Chemical denotes water MESH:D014867
215 4162-4167 Chemical denotes water MESH:D014867
216 4420-4425 Chemical denotes water MESH:D014867
217 4879-4884 Chemical denotes rutin MESH:D012431
221 5583-5584 Gene denotes τ Gene:4137
222 5625-5626 Gene denotes τ Gene:4137
223 5840-5848 Chemical denotes hydrogen MESH:D006859
226 7440-7445 Gene denotes spike Gene:43740568
227 7242-7250 Chemical denotes hydrogen MESH:D006859
230 7735-7740 Gene denotes spike Gene:43740568
231 8403-8406 Disease denotes VMD

LitCovid-sentences

Id Subject Object Predicate Lexical cue
T58 0-2 Sentence denotes 2.
T59 4-24 Sentence denotes Material and methods
T60 26-30 Sentence denotes 2.1.
T61 32-76 Sentence denotes Preparation of protein and ligand structures
T62 77-255 Sentence denotes The spike protein and main protease regulatory enzyme of SARS-CoV-2 have been revealed to play a vital role in COVID-19 infection in the host (Ke et al., 2020; Xue et al., 2008).
T63 256-395 Sentence denotes In order to delineate the drug treatment, the deduced three dimensional structures of target SAR-CoV-2 spike protein in open state (PDB ID:
T64 396-428 Sentence denotes 6VYB) and main protease (PDB ID:
T65 429-500 Sentence denotes 6LU7) were retrieved from RCSB Protein Data Bank (Burley et al., 2019).
T66 501-625 Sentence denotes The crystal structures of target proteins were imported to Schrödinger Maestro (Moore, 2015) for molecular docking analysis.
T67 626-909 Sentence denotes Pre-processing and preparation of target proteins were performed using Schrödinger Protein Preparation Wizard (Schrödinger, 2011) by adding the missing hydrogen atoms, correcting the bond orders, capping the protein termini, creating disulfide bonds and removing the water molecules.
T68 910-1046 Sentence denotes Also, the H-bonds were optimized and further the target proteins were equilibrated using OPLS 2005 force field (Robertson et al., 2015).
T69 1047-1212 Sentence denotes The library of ligands was downloaded from DrugBank (Wishart et al., 2018) and the coordinate files were prepared and optimized using LigPrep module (Release, 2017).
T70 1213-1362 Sentence denotes The energy minimization of ligand structures was carried using OPLS 2005 force field and ionization states were generated at pH 7.0 ± 2.0 using Epik.
T71 1363-1505 Sentence denotes This generated an output file with various stereoisomers and tautomeric conformers of each ligand producing chemical and structural diversity.
T72 1507-1511 Sentence denotes 2.2.
T73 1513-1576 Sentence denotes Determination of binding pocket and generation of receptor grid
T74 1577-1846 Sentence denotes The active sites enclosed in the binding pocket of spike protein and main protease were predicted using Computed Atlas of Surface Topography of proteins (CASTp) webserver (Tian et al., 2018) which calculates geometric and topological measurements of protein structures.
T75 1847-1982 Sentence denotes It measures the volume and surface area of the binding pocket and also predicts the atoms involved in formation of this binding cavity.
T76 1983-2191 Sentence denotes Although the active sites of spike protein and the main protease are known but still research is undergoing in which it is predicted that new amino acids might be involved in the inhibition of virus activity.
T77 2192-2289 Sentence denotes In order to undertake all the possibilities, binding pocket analysis was performed through CastP.
T78 2290-2444 Sentence denotes Further for the ease of molecular docking, a receptor grid was generated around the active sites of target proteins using Receptor Grid generation module.
T79 2445-2544 Sentence denotes The receptor grid file was created with a grid box around the centroid of selected active residues.
T80 2546-2550 Sentence denotes 2.3.
T81 2552-2601 Sentence denotes Protein ligand interactions and molecular docking
T82 2602-2761 Sentence denotes Protein ligand docking was conducted using GLIDE module of Schrödinger (Release, 2018) which performs all the docking calculations using OPLS 2005 force field.
T83 2762-2901 Sentence denotes A total of 2652 FDA approved drugs were screened against spike protein and main protease of SAR-CoV-2 through molecular docking approaches.
T84 2902-3263 Sentence denotes The virtual screening of compounds against the target protein was conducted using two docking methodologies, initially through a rapid screening of large set of compounds using high throughput virtual screening (HTVS) method followed by further screening a subset of top scoring HTVS compounds with a more precise and accurate extra precise (XP) docking method.
T85 3264-3387 Sentence denotes Protein ligand complexes were ranked using GlideScore function to predict the binding efficacy of ligands with the protein.
T86 3388-3567 Sentence denotes The docked complex with the lowest docking score was selected for further molecular dynamic simulation analysis to elucidate the inhibition mechanism against SARS-CoV-2 infection.
T87 3569-3573 Sentence denotes 2.4.
T88 3575-3649 Sentence denotes Molecular dynamics trajectory analysis of protein and their docked complex
T89 3650-3811 Sentence denotes The SARS-CoV-2 spike protein and main protease were used separately for molecular dynamics (MD) simulations alone and in complex with the repurposed drug, rutin.
T90 3812-4025 Sentence denotes All the four MD simulations were executed through GROMACS v5.0 under the force field GROMOS96 54a7 having water model SPC216 along with the time step of 1 fs for 100 ns (Abraham et al., 2015; Darden et al., 1993).
T91 4026-4198 Sentence denotes Varied sizes of the simulation box were created for each MD simulation event, which were further loaded with about respective amount of water molecules using the SPC model.
T92 4199-4489 Sentence denotes The total charge on spike protein, main protease and the two in complex with rutin were neutralized by adding –6, –4, –6, and –4 charges, respectively, and were incorporated into the simulation system by compensating the water molecules in the arbitrary locations inside the simulation box.
T93 4490-4592 Sentence denotes The NPT ensembles, along with periodic boundary conditions, were utilized to carry out MD simulations.
T94 4593-4669 Sentence denotes A cut-off of about 12 Å was used in order to manage the Vander Waals forces.
T95 4670-4817 Sentence denotes The Particle Mesh Ewald model manifesting a cut-off of 14 Å was further utilized to calculate the electrostatic interactions (Darden et al., 1993).
T96 4818-4947 Sentence denotes The spike protein, main protease and the two in complex with rutin were solvated through a slab of about 10 Å in every direction.
T97 4948-5002 Sentence denotes The neighbor list was updated to a frequency of 10 ps.
T98 5003-5083 Sentence denotes The MD simulations were achieved for each system employing the four major steps.
T99 5084-5273 Sentence denotes The first step deals with the energy minimization of the entire system utilizing the integrator of steepest descent in continuation with second integrator of conjugate gradients algorithms.
T100 5274-5504 Sentence denotes The second step involves the minimization and molecular dynamics of NVT and NPT ensembles for 500 ps and 1000 ps, respectively allowing the solvents and ions to evolve by keeping the same starting configuration for the structures.
T101 5505-5706 Sentence denotes In the third step the systems were heated using a lower temperature coupling (τ = 0.1 ps) along with pressure coupling (τ = 0.5 ps) to attain equilibrium at 300 K and 1 atm of temperature and pressure.
T102 5707-5835 Sentence denotes In the equilibration phase, the thermostat and barostat were evaluated through the Berendsen algorithm (Berendsen et al., 1984).
T103 5836-5947 Sentence denotes The hydrogen-containing bond lengths were constrained with the help of the LINCS algorithm (Hess et al., 1997).
T104 5948-6179 Sentence denotes Finally, the last step also called as the production step was carried out, where the MD simulation for 100 ns at 300 K temperature with 2 fs of time step were performed for both systems, and the last final structures were achieved.
T105 6180-6278 Sentence denotes The Maxwell Boltzmann distribution was utilized in order to reassign the velocities at every step.
T106 6279-6441 Sentence denotes The Nose Hoover thermostat and Parrinello Rahman barostat were the respective thermostat and barostat for the final MD or production run (Berendsen et al., 1984).
T107 6442-6528 Sentence denotes Various analyses were performed with the help of inbuilt analysis commands of GROMACS.
T108 6529-6772 Sentence denotes The root mean square deviation (RMSD) is a magnitude of the dimensional disparity among the two stagnant structures, and RMSD calculation is achieved depending upon the native structure and each consecutive trajectory frames in the simulation.
T109 6773-6981 Sentence denotes In addition, root mean square fluctuation (RMSF) profile measures the affability of every protein residue depending on the fluctuation about an average location within all MD simulations (Knapp et al., 2011).
T110 6982-7100 Sentence denotes Therefore, RMSD and RMSF of each simulation system were determined to examine the stability and residual fluctuations.
T111 7101-7231 Sentence denotes Further, the radius of gyration (Rg) analysis was performed to evaluate the compactness of both the simulation systems separately.
T112 7232-7521 Sentence denotes Also, the hydrogen bond analysis was performed to check the neighboring interactions with both simulation systems separately, including the hydrophobic interactions with the help of the LigPlot tool for both spike protein and main protease complexes with rutin before and after simulation.
T113 7522-7667 Sentence denotes Additionally, the solvent accessibility surface area (SASA) was also computed to examine the solvent attributable areas of all simulation system.
T114 7668-7914 Sentence denotes The cluster analysis having a cut-off value of 0.25 and 0.2 nm for spike protein and main protease respectively, depending upon the RMSD profile were utilized to demonstrate the conformations found utmost intermittently throughout the trajectory.
T115 7915-8052 Sentence denotes Here, all the structures having RMSD values of below 0.25 nm for all components within a cluster are incorporated to the initial cluster.
T116 8053-8186 Sentence denotes It is rare that a molecule having a higher value for RMSD than 0.25 nm from other cluster supposedly would be treated as a structure.
T117 8187-8284 Sentence denotes The secondary structure analysis was also performed using the DSSP program (Martin et al., 2005).
T118 8285-8474 Sentence denotes The visualization of protein nature during the entire simulation was accomplished by using Visual Molecular Dynamics (VMD) (Humphrey et al., 1996) and UCSF Chimera (Pettersen et al., 2004).