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PMC:7544943 JSONTXT 17 Projects

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Id Subject Object Predicate Lexical cue
T1 0-76 Sentence denotes In silico investigation of spice molecules as potent inhibitor of SARS-CoV-2
T2 77-79 Sentence denotes J.
T3 80-91 Sentence denotes Rout et al.
T4 92-138 Sentence denotes Journal of Biomolecular Structure and Dynamics
T5 140-148 Sentence denotes Abstract
T6 149-157 Sentence denotes Abstract
T7 158-277 Sentence denotes The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel infectious disease that is in rapid growth.
T8 278-353 Sentence denotes Several trials are going on worldwide to find a solution for this pandemic.
T9 354-540 Sentence denotes The viral replication can be blocked by inhibiting the receptor-binding domain (RBD) of SARS-CoV-2 spike protein (SARS-CoV-2 RBD Spro) and the SARS-CoV-2 main protease (SARS-CoV-2 Mpro).
T10 541-659 Sentence denotes The binding of potential small molecules to these proteins can inhibit the replication and transcription of the virus.
T11 660-762 Sentence denotes The spice molecules that are used in our food have antiviral, antifungal and antimicrobial properties.
T12 763-895 Sentence denotes As spice molecules are consumed in the diet, hence its antiviral properties against SARS-CoV-2 will benefit in a significant manner.
T13 896-1098 Sentence denotes Therefore, in this work, the molecular docking of 30 selected spice molecules (screened through ADME property) was performed to identify the potential inhibitors for the RBD Spro and Mpro of SARS-CoV-2.
T14 1099-1274 Sentence denotes We have found that though all the molecules bind actively with the SARS-CoV-2 RBD Spro and Mpro, but Piperine has the highest binding affinity among the 30 screened molecules.
T15 1275-1385 Sentence denotes Besides, the comparative study between Piperine and currently used drugs show that Piperine is more effective.
T16 1386-1508 Sentence denotes The interaction of Piperine with RBD Spro and Mpro is further validated by the molecular dynamics (MD) simulation studies.
T17 1509-1649 Sentence denotes The free energy landscape and binding free energy results also, support for the stable complex formation of Piperine with RBD Spro and Mpro.
T18 1650-1801 Sentence denotes We anticipate immediate wet-lab experiments and clinical trials in support of this computational study that might help to inhibit the SARS-CoV-2 virus.
T19 1802-1830 Sentence denotes Communicated by Ramaswamy H.
T20 1831-1836 Sentence denotes Sarma
T21 1838-1856 Sentence denotes Graphical Abstract
T22 1858-1860 Sentence denotes 1.
T23 1862-1874 Sentence denotes Introduction
T24 1875-1990 Sentence denotes The novel coronavirus disease 2019 (COVID-19) has become a major threat worldwide due to its fast-spreading nature.
T25 1991-2078 Sentence denotes This disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
T26 2079-2205 Sentence denotes The entry of this coronavirus to the host cell is mediated through the transmembrane spike glycoproteins (Hasan et al., 2020).
T27 2206-2507 Sentence denotes This glycoprotein consists of two subunits and is reported to have a similar affinity to the human angiotensin-converting enzyme 2 (ACE2) as that of the severe acute respiratory syndrome coronavirus (SARS-CoV), which in turn results in efficient spreading of SARS-CoV-2 in humans (Walls et al., 2020).
T28 2508-2675 Sentence denotes The spike glycol protein binds to its receptor human ACE2 by its receptor-binding domain (RBD) and is activated proteolytically by human protease (Shang et al., 2020).
T29 2676-2876 Sentence denotes The interaction of the RBD of the spike glycoprotein to ACE2 is carried out by ARG403, TYR453, SER494, TYR495, PHE497, GLN498, THR500, ASN501, TYR505 residues of spike glycoprotein (Lan et al., 2020).
T30 2877-3019 Sentence denotes The interaction of RBD Spro to ACE2 can be inhibited by the small molecules that interact with the above residues of RBD spike protein (Spro).
T31 3020-3236 Sentence denotes On the other hand, the SARS-CoV-2 main protease (Mpro), also known as chymotrypsin-like protease, or 3-C-like protease (3CLpro), plays a vital role in processing the polyproteins through the translation of viral RNA.
T32 3237-3367 Sentence denotes This protease is reported to have a minimum of 11 cleavage sites resulting in viral replication and toxicity (Zhang et al., 2020).
T33 3368-3470 Sentence denotes The inhibition of these two viral targets can actively block the fusion and replication of SARS-CoV-2.
T34 3471-3656 Sentence denotes Currently, researchers are working globally for finding treatment for this disease in identifying a specific drug or vaccine that can inhibit viral replication at the earliest possible.
T35 3657-3973 Sentence denotes The devastation of this disease is vividly seen from the data on the WHO website, which shows the infected patient number more than 245 lakhs and casualties more than 8 lakhs, worldwide from 216 countries, and still, it is continuing (https://www.who.int/emergencies/diseases/novel-coronavirus-2019, 29 August 2020).
T36 3974-4189 Sentence denotes Currently, there are no approved drugs and vaccines for the treatment of COVID-19, but a few drugs such as remdesivir, hydroxychloroquine, etc. are under restricted use in case of emergency (Magagnoli et al., 2020).
T37 4190-4421 Sentence denotes Meanwhile, the computational tools, molecular docking and molecular dynamics (MD) have gained attention as essential tools to investigate potential inhibitor molecules (Anurag et al., 2020; Gupta et al., 2020; Sourav et al., 2020).
T38 4422-4573 Sentence denotes Choy et al. reported in-vitro studies showing remdesivir, lopinavir, emetine and homoharringtonine inhibits SARS-CoV-2 replication (Choy et al., 2020).
T39 4574-4706 Sentence denotes Similarly, Wang et al. reported the inhibition property of remdesivir and chloroquine against novel coronavirus (Wang et al., 2020).
T40 4707-4822 Sentence denotes In addition to different drug compounds, researchers also searched for natural molecules having antiviral activity.
T41 4823-4925 Sentence denotes Natural constituents from foods, spices, herbs are also being found to have anti-infective properties.
T42 4926-5126 Sentence denotes In this context, small active molecules present in natural products and their derivatives have gained tremendous attention as a source of therapeutic agents due to structural diversity for many years.
T43 5127-5331 Sentence denotes From 1940 to 2014, the US Food and Drug Administration (FDA) has approved about 49% of all small molecules that are natural products or derivates linked directly to those molecules (Newman & Cragg, 2016).
T44 5332-5475 Sentence denotes The compound of essential garlic oil, a spice used in food, is reported as an inhibitor using the molecular docking method (Thuy et al., 2020).
T45 5476-5642 Sentence denotes There are several recent studies on the inhibition of SARS-CoV-2 using many different natural and antiviral molecules (Al-Khafaji et al., 2020; Joshi et al., 2020; D.
T46 5643-5699 Sentence denotes Kumar, Kumari, et al., 2020; Muralidharan et al., 2020).
T47 5700-5836 Sentence denotes Recently, Das et al., using blind molecular docking, investigated for the potential inhibitors of SARS-CoV-2 Mpro (Sourav et al., 2020).
T48 5837-5983 Sentence denotes Molecules studied by Das et al. are drug molecules, antivirals, antifungals, anti-nematodals and anti-protozoals in addition to natural compounds.
T49 5984-6176 Sentence denotes Besides, natural molecules such as alkaloids and terpenoids from African medicinal plants were studied by Gyebi et al. for the inhibition property against SARS-CoV-2 Mpro (Gyebi et al., 2020).
T50 6177-6299 Sentence denotes Recently, Umesh et al. screened compounds from Indian spices as potent inhibitors of SARS-CoV-2 Mpro (Umesh et al., 2020).
T51 6300-6580 Sentence denotes Every spice has a particular aroma, colour and flavour due to the presence of specific molecules in them, and also, have antiviral properties (Aboubakr et al., 2016; Astani et al., 2010; Brochot et al., 2017; Chang et al., 2013; Choi, 2016; Mair et al., 2016; Zhang et al., 2014).
T52 6581-6848 Sentence denotes These properties of the spice molecules compel us to conduct the present study, where we investigated the inhibition property of molecules present in various spices against the SARS-CoV-2 RBD Spro and SARS-Cov-2 Mpro using molecular docking and MD simulation studies.
T53 6849-6950 Sentence denotes The compounds tested and their source of origin with PubChem ID are listed in Supplementary Table S1.
T54 6951-6959 Sentence denotes Table 1.
T55 6961-7094 Sentence denotes Predicted data of docking score, solubility, pharmacokinetics, drug-likeness and medicinal chemistry of the screened spice molecules.
T56 7095-7098 Sentence denotes Sl.
T57 7099-7102 Sentence denotes No.
T58 7104-7287 Sentence denotes Molecule Binding energy (kcal/mol) ESOL Log S Ali Log S Silicos-IT LogSw GI absorption BBB permeant Pgp substrate Log Kp (cm/s) Bioavailability score Synthetic accessibility
T59 7288-7302 Sentence denotes Mpro RBD Spro
T60 7303-7387 Sentence denotes 1 2-Decenoic acid –5.4 –4.6 –2.8 –4.23 –2.15 High Yes No –4.68 0.56 2.44
T61 7388-7476 Sentence denotes 2 α-Terpinyl acetate –5.5 –5.0 –3.35 –4.21 –2.36 High Yes No –4.69 0.55 3.13
T62 7477-7555 Sentence denotes 3 Capsaicin –6.4 –5.5 –3.53 –4.5 –4.87 High Yes No –5.62 0.55 2.32
T63 7556-7633 Sentence denotes 4 Carvone –6.2 –5.2 –2.41 –2.72 –2.16 High Yes No –5.29 0.55 3.33
T64 7634-7717 Sentence denotes 5 Cinnamaldehyde –5.7 –5.1 –2.17 –1.88 –2.4 High Yes No –5.76 0.55 1.65
T65 7718-7800 Sentence denotes 6 Cuminaldehyde –5.9 –5.1 –2.52 –2.37 –3.15 High Yes No –5.52 0.55 1.0
T66 7801-7888 Sentence denotes 7 Dipropyl disulfide –3.1 –3.0 –2.14 –3.42 –2.48 High Yes No –5.3 0.55 2.79
T67 7889-7968 Sentence denotes 8 Eucalyptol –5.2 –4.9 –2.52 –2.59 –2.45 High Yes No –5.3 0.55 3.65
T68 7969-8046 Sentence denotes 9 Linalool –5.5 –4.9 –2.4 –3.06 –1.84 High Yes No –5.13 0.55 2.74
T69 8047-8126 Sentence denotes 10 Vanillin –5.7 –4.8 –1.82 –1.78 –1.88 High Yes No –6.37 0.55 1.15
T70 8127-8202 Sentence denotes 11 Thymol –5.8 –5.3 –3.19 –3.4 –3.01 High Yes No –4.87 0.55 1.0
T71 8203-8290 Sentence denotes 12 Sabinene hydrate –5.2 –4.7 –2.07 –2.18 –1.91 High Yes No –5.74 0.55 2.82
T72 8291-8369 Sentence denotes 13 Piperine –7.3 –6.4 –3.74 –3.96 –3.0 High Yes No –5.58 0.55 2.92
T73 8370-8447 Sentence denotes 14 Menthol –5.6 –5.2 –2.88 –3.5 –1.48 High Yes No –4.84 0.55 2.63
T74 8448-8526 Sentence denotes 15 Eugenol –6.0 –5.0 –2.46 –2.53 –2.79 High Yes No –5.69 0.55 1.58
T75 8527-8607 Sentence denotes 16 Estragole –5.7 –4.8 –3.09 –3.24 –3.35 High Yes No –4.81 0.55 1.28
T76 8608-8687 Sentence denotes 17 Gingerol –6.1 –5.5 –2.96 –3.82 –4.58 High Yes No –6.14 0.55 2.81
T77 8688-8764 Sentence denotes 18 Shogaol –5.8 –5.4 –3.7 –4.67 –4.8 High Yes No –5.15 0.55 2.51
T78 8765-8843 Sentence denotes 19 Paradol –6.0 –4.6 –3.72 –4.79 –5.52 High Yes No –5.08 0.55 2.28
T79 8844-8921 Sentence denotes 20 Zingerone –6.0 –5.1 –1.8 –1.68 –3.1 High Yes No –6.7 0.55 1.52
T80 8922-8999 Sentence denotes 21 Borneol –5.7 –4.3 –2.51 –2.8 –1.91 High Yes No –5.31 0.55 3.43
T81 9000-9085 Sentence denotes 22 Bornyl acetate –5.3 –4.8 –3.63 –4.57 –2.58 High Yes No –4.44 0.55 3.64
T82 9086-9163 Sentence denotes 23 Citral –5.5 –4.7 –2.43 –3.05 –1.96 High Yes No –5.08 0.55 2.49
T83 9164-9246 Sentence denotes 24 Citronellal –4.8 –4.8 –2.88 –3.88 –2.33 High Yes No –4.52 0.55 2.57
T84 9247-9330 Sentence denotes 25 2-Undecanone –4.9 –4.3 –2.94 –4.15 –3.83 High Yes No –4.43 0.55 1.72
T85 9331-9416 Sentence denotes 26 Geranyl acetate –5.4 –4.8 –3.21 –4.3 –2.52 High Yes No –4.63 0.55 2.72
T86 9417-9496 Sentence denotes 27 Nerolidol –5.8 –5.0 –3.8 –4.99 –3.15 High Yes No –4.23 0.55 3.53
T87 9497-9581 Sentence denotes 28 Terpinen-4-ol –5.2 –5.5 –2.78 –3.36 –1.91 High Yes No –4.93 0.55 3.28
T88 9582-9662 Sentence denotes 29 Terpineol –5.7 –5.2 –2.87 –3.49 –1.69 High Yes No –4.83 0.55 3.24
T89 9663-9741 Sentence denotes 30 Decanal –4.7 –3.9 –2.67 –3.85 –3.44 High Yes No –4.56 0.55 1.62
T90 9743-9745 Sentence denotes 2.
T91 9747-9768 Sentence denotes Materials and methods
T92 9769-9890 Sentence denotes In general, molecular modelling is implemented as an essential tool for the prediction of drug–macromolecule interaction.
T93 9891-9993 Sentence denotes This technique helps to enhance the success rate of an experiment and cuts down the experimental cost.
T94 9994-10133 Sentence denotes Hence, the molecular docking study can help to analyse the possible binding pose of a small molecule on the active site of a macromolecule.
T95 10134-10265 Sentence denotes Here we used molecular docking to screen some biologically active spice molecules with the SARS-CoV-2 RBD Spro and SARS-Cov-2 Mpro.
T96 10266-10388 Sentence denotes The molecule with the highest binding affinity to RBD Spro and Mpro was subjected to MD simulation for further validation.
T97 10390-10394 Sentence denotes 2.1.
T98 10396-10443 Sentence denotes Drug-likeness properties of the small molecules
T99 10444-10562 Sentence denotes The property of the small molecules for drug-likeness was estimated using the Lipinski’s rule (Lipinski et al., 2001).
T100 10563-10784 Sentence denotes This rule works on five parameters viz. no more than five hydrogen bond donors, no more than 10 hydrogen bond acceptors, molecular mass <500 Da, and the octanol-water partition coefficient, i.e. log P should not exceed 5.
T101 10785-10905 Sentence denotes The Lipinski’s parameters were obtained by using the SwissADME server (www.swissadme.ch/index.php) (Daina et al., 2017).
T102 10907-10911 Sentence denotes 2.2.
T103 10913-10962 Sentence denotes Structure preparation of the proteins and ligands
T104 10963-11017 Sentence denotes The crystal structures of the SARS-CoV-2 Spro (PDB ID:
T105 11018-11052 Sentence denotes 6M0J) and SARS-CoV-2 Mpro (PDB ID:
T106 11053-11105 Sentence denotes 6Y84) were obtained from the RCSB protein data bank.
T107 11106-11224 Sentence denotes All the non-standard residues, including water, were removed from the PDB file using Chimera (Pettersen et al., 2004).
T108 11225-11290 Sentence denotes The RBD domain was obtained from the PDB file of SARS-Cov-2 Spro.
T109 11291-11399 Sentence denotes The RBD Spro residue sequence number before and after removing ACE2 is presented in Supplementary Figure S1.
T110 11400-11628 Sentence denotes The 3D conformers of the ligands were obtained from the PubChem and optimized using the steepest descent and conjugate gradient steps with General Amber Force Field (GAFF) (Wang et al., 2004) in Chimera (Pettersen et al., 2004).
T111 11629-11638 Sentence denotes Figure 1.
T112 11640-11745 Sentence denotes Predicted lipophilicity (Log P) values of the spice molecules obtained from different calculation models.
T113 11747-11751 Sentence denotes 2.3.
T114 11753-11776 Sentence denotes Molecular docking study
T115 11777-11914 Sentence denotes The prepared structures of the protein and ligand were subjected to molecular docking analysis using AutoDock Vina (Trott & Olson, 2010).
T116 11915-12010 Sentence denotes AutoDock Vina is the newest member of the AutoDock family that has improved speed and accuracy.
T117 12011-12154 Sentence denotes It uses a hybrid scoring function and a quasi-Newtonian optimization algorithm to find the lowest energy confirmations within the search space.
T118 12155-12272 Sentence denotes A grid box of 40 Å × 65 Å × 70 Å was built with the centre of the box at (11.98, 0.60, 4.79) for the SARS-CoV-2 Mpro.
T119 12273-12389 Sentence denotes A grid box of size 30 Å × 45 Å × 30 Å with centre at (−36.51, 30.69, 5.48) was prepared for the SARS-CoV-2 RBD Spro.
T120 12390-12567 Sentence denotes The exhaustiveness of search was set at 20 and 8 for the SARS-CoV-2 Mpro and the SARS-CoV-2 RBD Spro, respectively, to compensate for the larger box volume and reliable results.
T121 12568-12659 Sentence denotes The docked poses were ranked as per their binding affinities at the end of the docking run.
T122 12660-12801 Sentence denotes The ligand interactions of the best-docked poses at the active sites of the macromolecule were extracted using PyMol (Schrödinger LLC, 2017).
T123 12802-12912 Sentence denotes The ligand interactions were analysed using the 2D interaction plot in the Discovery Studio Visualizer (2005).
T124 12913-13050 Sentence denotes The Coulombic electrostatic potential surface was determined with the help of the APBS plugin available in PyMol (Schrödinger LLC, 2017).
T125 13052-13056 Sentence denotes 2.4.
T126 13058-13098 Sentence denotes Molecular dynamics (MD) simulation study
T127 13099-13374 Sentence denotes To verify the stability of the complex and interaction dynamics of SARS-CoV-2 RBD Spro and SARS-CoV-2 Mpro, we performed the MD simulation study of the two complexes with the highest docking score (Spro-Piperine and Mpro-Piperine), using GROMACS-5.1.5 (Abraham et al., 2015).
T128 13375-13468 Sentence denotes The CHARMM36 forcefield (Huang & MacKerell, 2013) was used for the simulation of the systems.
T129 13469-13578 Sentence denotes The topology parameters for the ligand molecule were obtained from CGenFF (Vanommeslaeghe & MacKerell, 2012).
T130 13579-13675 Sentence denotes A dodecahedron simulation box filled with TIP3P water model (Price & Brooks, 2004) was prepared.
T131 13676-13752 Sentence denotes Counter ions were added to maintain the electrical neutrality of the system.
T132 13753-13811 Sentence denotes The systems were kept at a buffer concentration of 0.15 M.
T133 13812-13913 Sentence denotes Then, the build systems were energy minimized with 50,000 steps using the steepest descent algorithm.
T134 13914-14054 Sentence denotes Then the systems were equilibrated under NVT and NPT ensembles for 100 ps at 300 K temperature and 1 atm pressure before the production run.
T135 14055-14147 Sentence denotes After the equilibration, a production run of 100 ns was incorporated under the NPT ensemble.
T136 14148-14310 Sentence denotes For long-range electrostatic interaction, particle mesh Ewald (PME) (Darden et al., 1993) and for van der Waals interactions, the force-switching scheme was used.
T137 14311-14541 Sentence denotes Besides, for temperature and pressure coupling, the Berendsen thermostat (Berendsen et al., 1984) with velocity rescaling and Parrinello-Rahman barostat (Parrinello & Rahman, 1981) with isotropic rescaling were used, respectively.
T138 14542-14634 Sentence denotes The simulation time step was set to 2 fs, and the trajectories were recorded at every 10 ps.
T139 14635-14840 Sentence denotes The simulation data were analysed by analysing the root mean square deviation (RMSD), root mean square fluctuation (RMSF), number of hydrogen bonds and radius of gyration (Rg) using Gromacs analysis tools.
T140 14841-14950 Sentence denotes The principal component analysis (PCA) was performed using the g_covar, g_anaeig and g_sham tools of Gromacs.
T141 14951-15030 Sentence denotes The data were exported to origin 9.0 and plotted for further analysis purposes.
T142 15032-15036 Sentence denotes 2.5.
T143 15038-15077 Sentence denotes Mm/PBSA binding free energy calculation
T144 15078-15239 Sentence denotes The method of calculation of binding free energy from MD trajectory snapshots using the molecular mechanics Poisson–Boltzmann surface area method is widely used.
T145 15240-15431 Sentence denotes The binding free energy of the systems was estimated by extracting the snaps from the last 20 ns of the MD simulation using g_mmpbsa tool of Gromacs (Baker et al., 2001; Kumari et al., 2014).
T146 15432-15563 Sentence denotes The binding free energy takes the contribution from vacuum potential energy, polar solvation energy and non-polar solvation energy.
T147 15564-15781 Sentence denotes The binding free energy can be represented as (1) ΔGbind=Gcomplex−(Gprotein+Gligand) where Gcomplex, Gprotein and Gligand are the total free energies of the complex, isolated protein and isolated ligand, respectively.
T148 15782-16018 Sentence denotes The free energy of the individual terms was estimated by (2) Gx=EMM−TS+Gsolvation where x is the complex, protein or ligand, and TS represents the entropic contribution to free energy in a vacuum with T and S as temperature and entropy.
T149 16019-16372 Sentence denotes The average molecular mechanics potential and solvation free energies were calculated by using Equations (3) and (4) (3) EMM=Ebonded+Enonbonded= Ebonded−(Eelec+Evdw) (4) Gsolvation=Gpolar+Gnonpolar where Ebonded takes the contribution from a bond, angle and dihedral terms and Enonbonded consists of electrostatic and van der Waals energy contributions.
T150 16373-16539 Sentence denotes The solvation energy includes the polar and non-polar solvation energies from the Poisson–Boltzmann equation and solvent accessible surface area (SASA), respectively.
T151 16541-16543 Sentence denotes 3.
T152 16545-16567 Sentence denotes Results and discussion
T153 16569-16573 Sentence denotes 3.1.
T154 16575-16631 Sentence denotes Molecular electrostatic potential (MEP) surface analysis
T155 16632-16755 Sentence denotes The electrostatic potential is an essential property for the review and prediction of the reactive behaviour of a molecule.
T156 16756-17007 Sentence denotes The study of the MEP surface can provide information about the active site of the macromolecule with the indication of relative ligand orientation and nature of the active site at which an approaching electrophile is attracted (Politzer et al., 1985).
T157 17008-17155 Sentence denotes In a biological macromolecule, the electrostatic potential surface is plotted by analysing the electron-rich and deficient regions of the molecule.
T158 17156-17319 Sentence denotes The detailed insight at the molecular label helps to predict the potentiality of the ligands to take part in chemical reactions and their mechanism of interaction.
T159 17320-17499 Sentence denotes The MEP surface representation of SARS-CoV-2 RBD Spro and Mpro ligand-binding sites with the simultaneous presence of all docked molecules are provided in Supplementary Figure S2.
T160 17500-17694 Sentence denotes The electronically poor regions (blue) are referred to as positive potential, whereas the dense electron regions (red) are at a negative potential, and the white zones are considered as neutral.
T161 17695-17869 Sentence denotes From the figure, it is observed that most of the selected molecules actively bound at the red regions that are referred to as highly negative electrostatic potential regions.
T162 17870-18044 Sentence denotes This implies that the molecules are polar and can actively take part in the binding process with stable interactions, which in turn could help to block the viral replication.
T163 18045-18054 Sentence denotes Figure 2.
T164 18056-18158 Sentence denotes Predicted solubility (Log S) values of the spice molecules obtained from different calculation models.
T165 18160-18164 Sentence denotes 3.2.
T166 18166-18179 Sentence denotes Lipophilicity
T167 18180-18316 Sentence denotes Lipophilicity or fat friendliness of a molecule defines the dissolving capability in fat, oil or any non-polar solvent (Lindsley, 2010).
T168 18317-18440 Sentence denotes The water n-octanol partition coefficient (log Po/w) is used as the measure of lipophilicity (Constantinescu et al., 2019).
T169 18441-18569 Sentence denotes Various computational methods are developed for the estimation of log Po/w for diverse performance upon different chemical sets.
T170 18570-18905 Sentence denotes The SwissADME provides five different predictive models such as XLOGP3 (Cheng et al., 2007), WLOGP (Wildman & Crippen, 1999), MLOGP (Moriguchi et al., 1992), SILICOS-IT (http://silicos-it.be.s3-website-eu-west-1.amazonaws.com/software/filter-it/1.0.2/filter-it.html, 2016) and iLOGP (Daina et al., 2014) for better prediction accuracy.
T171 18906-19033 Sentence denotes Predicted lipophilicity (Log P) values of the spice molecules obtained from different calculation models are shown in Figure 1.
T172 19034-19267 Sentence denotes All the molecules subjected to lipophilicity test lie in the range of +1.2 to +4.19 of consensus value that obeys the Lipinski’s limit of log p < 5, which suggests they can be used for further clinical trials (Arnott & Planey, 2012).
T173 19268-19378 Sentence denotes The lowest lipophilicity is observed for Vanillin and the highest for Nerolidol, among the screened molecules.
T174 19379-19470 Sentence denotes From Figure 1, it is found that all the ligand molecules have positive lipophilicity value.
T175 19471-19546 Sentence denotes Hence, these molecules satisfy the essential criteria to be drug molecules.
T176 19548-19552 Sentence denotes 3.3.
T177 19554-19570 Sentence denotes Water solubility
T178 19571-19673 Sentence denotes Solubility (Log S) is the measure of homogeneity of the system from the mixture of solute and solvent.
T179 19674-19820 Sentence denotes It is considered as one of the vital parameters in drug concentration determination for a desired pharmacological response (Savjani et al., 2012).
T180 19821-19897 Sentence denotes Poor solubility of drugs is a major issue in drug discovery and development.
T181 19898-20034 Sentence denotes Solubility acts as a driving force to attain high drug concentration in blood for therapeutic effectiveness (Bergström & Larsson, 2018).
T182 20035-20128 Sentence denotes The drug solubility property of the proposed small molecules was obtained from the SwissADME.
T183 20129-20448 Sentence denotes The server used three solubility models, such as Ali (Ali et al., 2012), ESOL (Delaney, 2004) and Silicos-IT (http://silicos-it.be.s3-website-eu-west-1.amazonaws.com/software/filter-it/1.0.2/filter-it.html, 2016) that is comprised of different topological methods to check the water solubility of these small molecules.
T184 20449-20564 Sentence denotes The plot for solubility of the proposed small molecules based on these three different models is shown in Figure 2.
T185 20565-20766 Sentence denotes The Log S values obtained for the ligand molecules based on these three models are in the range of −1.8 to −3.94 for ESOL method, −1.68 to −4.99 for Ali method and −1.48 to −5.52 for Silicos-IT method.
T186 20767-20874 Sentence denotes The values from different models suggest to the moderately soluble to very soluble nature of the molecules.
T187 20875-21004 Sentence denotes The reference values of Log S for moderately soluble and highly soluble molecules range from −4 to −6 and −2 to −4, respectively.
T188 21005-21082 Sentence denotes The solubility values suggest for the oral administration of these molecules.
T189 21084-21088 Sentence denotes 3.4.
T190 21090-21116 Sentence denotes Pharmacokinetic properties
T191 21117-21252 Sentence denotes The pharmacokinetic property is the prime factor for the selection of a drug candidate that describes the drug disposition in the body.
T192 21253-21419 Sentence denotes The significant parameters that quantify the pharmacokinetics of a drug are its ADME (absorption, distribution, metabolism, excretion) properties (Jang et al., 2001).
T193 21420-21627 Sentence denotes All the molecules subjected to ADME tests are qualified for drug approval with their high value of gastrointestinal (GI) absorption (Daina & Zoete, 2016), which in turn implies for their use as an oral drug.
T194 21628-21710 Sentence denotes Table 1 represents the pharmacokinetic properties of the proposed drug candidates.
T195 21711-21848 Sentence denotes The passive GI absorption and blood–brain barrier (BBB) permeation is a fundamental criterion for the distribution of the drug molecules.
T196 21849-21974 Sentence denotes From Table 1, it is observed that all the ligand molecules are BBB permeant that implies their underlying distribution index.
T197 21975-22112 Sentence denotes The high negative skin permeable coefficient (Kp) values indicate a less skin permeability that is useful for their transdermal delivery.
T198 22113-22289 Sentence denotes The interaction of the drug molecules with cytochromes P450 (CYP) is an essential property as they play a crucial role in drug elimination through biotransformation metabolism.
T199 22290-22609 Sentence denotes The noninhibition of CYP isoforms such as CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4 disclose that these molecules are not the substrate for these enzymes that resembles for the lower degradation rate of these molecules, which will make it effectively available for blocking the SARS-CoV-2 RBD Spro and SARS-CoV-2 Mpro.
T200 22610-22693 Sentence denotes The synthetic accessibility values suggest the facile synthesis of these molecules.
T201 22694-22805 Sentence denotes All these parameters infer these close to drug-like molecules, which may be used as successful drug candidates.
T202 22807-22811 Sentence denotes 3.5.
T203 22813-22836 Sentence denotes Molecular docking study
T204 22838-22844 Sentence denotes 3.5.1.
T205 22846-22911 Sentence denotes Docking study of SARS-CoV-2 receptor-binding domain spike protein
T206 22912-23120 Sentence denotes In addition to the above investigations, a molecular docking study was performed to estimate the binding affinity and their binding pose of the ligand molecules at the binding site of the SARS-CoV-2 RBD Spro.
T207 23121-23232 Sentence denotes From the study, it is observed that Piperine has the highest interaction affinity among the screened compounds.
T208 23233-23482 Sentence denotes The docked poses of the four ligand molecules (Piperine, Capsaicin, Gingerol and Terpinen-4-ol) along with their 2D interaction diagram having the highest binding affinity, among the selected molecules, are presented in descending order in Figure 3.
T209 23483-23730 Sentence denotes From Table 1, it is observed that these four molecules follow the trend for their binding affinity with Piperine (−6.4 kcal/mol) at the highest, then Capsaicin, Ginerol and Terpinen-4-ol (all having −5.5 kcal/mol) among all the selected molecules.
T210 23731-23846 Sentence denotes From Figure 3(a), it is observed that Piperine is associated with hydrogen bond interaction with GLY164 and GLY170.
T211 23847-23968 Sentence denotes TYR173 (TYR505) and SER162 (SER494) are involved with pi–pi T-shaped and carbon-hydrogen bond interactions, respectively.
T212 23969-24137 Sentence denotes The binding process is also governed by van der Waals interactions with the residues ARG71, TYR121 (TYR453), TYR163 (TYR495) and ASN169 (ASN501) of SARS-CoV-2 RBD Spro.
T213 24138-24315 Sentence denotes Hence, the interaction of Piperine with SARS-CoV-2 RBD Spro is stabilized by covalent hydrogen bonding, pi–pi T-shaped and van der Waals interactions with a good affinity score.
T214 24316-24494 Sentence denotes Capsaicin interacts with the residues GLY164 and TYR173 (TYR505) through pi-Donor hydrogen bond and pi–pi T-shaped interactions with the benzene ring, respectively (Figure 3(b)).
T215 24495-24681 Sentence denotes The residues ARG71 (ARG403), ASP73, GLU74, GLN77, LYS85, TYR121 (TYR453), SER162 (SER494), TYR163 (TYR495) and ASN169 (ASN501) are involved with van der Waals interaction with Capsaicin.
T216 24682-24691 Sentence denotes Figure 3.
T217 24693-24844 Sentence denotes Lowest energy docked pose of (a) Piperine, (b) Capsaicin, (c) Gingerol and (d) Terpinen-4-ol with SARS-Cov-2 RBD Spro and their 2D interaction diagram.
T218 24845-24899 Sentence denotes The colour codes represent the nature of interactions.
T219 24900-25018 Sentence denotes On the other hand, Gingerol is stabilized by various kinds of interactions with the SARS-CoV-2 RBD Spro (Figure 3(c)).
T220 25019-25127 Sentence denotes The residues GLY164, ASN169 (ASN501) and GLY170 are associated with hydrogen bond interaction with Gingerol.
T221 25128-25402 Sentence denotes Other than the hydrogen bond interaction TYR173 (TYR505) is having a pi–pi T-shaped interaction with the benzene ring of Gingerol while ARG71 (ARG403), TYR121 (TYR453), TYR163 (TYR495), PHE165 (PHE497) and GLN166 (GLN498) residues are involved in van der Waals interactions.
T222 25403-25659 Sentence denotes The Terpinen-4-ol is stabilized by hydrophobic interaction with the residues ARG125, LYS126, TYR141 and PRO159 while the residues ARG122, PHE124, ASP135, SER137, GLU139 and ILE140 are involved in van der Waals interactions with Terpinen-4-ol (Figure 3(d)).
T223 25660-25790 Sentence denotes The lowest energy poses of the rest 26 molecules along with their 2D interaction diagrams are provided in Supplementary Figure S3.
T224 25792-25798 Sentence denotes 3.5.2.
T225 25800-25841 Sentence denotes Docking study of SARS-CoV-2 main protease
T226 25842-25965 Sentence denotes The above-selected molecules were also docked with the SARS-CoV-2 Mpro to observe the inhibitory effect of these molecules.
T227 25966-26086 Sentence denotes The docking study reveals that all the molecules are interacting with the SARS-CoV-2 Mpro with certain binding affinity.
T228 26087-26134 Sentence denotes The docking data are also presented in Table 1.
T229 26135-26324 Sentence denotes From Table 1, it is seen that Piperine has the highest affinity at the binding site of SARS-CoV-2 Mpro among all the selected molecules, which is similar to the case of SARS-CoV-2 RBD Spro.
T230 26325-26516 Sentence denotes The ΔG value, known as binding free energy, for the four molecules having the highest affinity among all the selected molecules, along with their 2D interaction diagram, is given in Figure 4.
T231 26517-26686 Sentence denotes The four molecules have followed the binding affinity trend as Piperine (−7.3 kcal/mol) > Capsaicin (−6.4 kcal/mol) > Carvone (−6.2 kcal/mol) > Gingerol (−6.1 kcal/mol).
T232 26687-26877 Sentence denotes From Figure 4(a), it is observed that the interaction of Piperine at the binding site of the SARS-CoV-2 Mpro is stabilized by hydrogen bonding, electrostatics and van der Waals interactions.
T233 26878-27082 Sentence denotes The residues GLN299 and VAL303 are associated with hydrogen bonding interaction; ASP295 and ARG298 with charged interactions while MET6 and PRO9 are associated with hydrophobic interactions with Piperine.
T234 27083-27247 Sentence denotes The molecule is also stabilized through van der Waals interactions with residues PHE8, GLY127, ILE152, PHE291 and THR304 at the binding site of the SARS-CoV-2 Mpro.
T235 27248-27372 Sentence denotes The molecule Capsaicin is stabilized in the binding pocket through van der Waals and hydrophobic interactions (Figure 4(b)).
T236 27373-27509 Sentence denotes The residues MET6, PHE8, PRO9 and ILE152 are interacting through hydrophobic interactions such as alkyl and pi–alkyl with the Capsaicin.
T237 27510-27669 Sentence denotes Capsaicin is interacting with residues ALA7, GLY11, LYS12, GLN127, TYR154, PHE291, ASP295, ARG298, GLN299, VAL303 and THR304 through van der Waals interaction.
T238 27670-27801 Sentence denotes The interaction of Carvone with the SARS-CoV-2 Mpro is stabilized through hydrophobic and van der Walls interactions (Figure 4(c)).
T239 27802-27908 Sentence denotes Carvone interacts with the residues MET6, PHE8 and ARG298 of SARS-CoV-2 Mpro through hydrophobic contacts.
T240 27909-28023 Sentence denotes The residues ALA7, PRO9, GLN127, ASP295, GLN299, GLY302 and VAL303 are in van der Waals interactions with Carvone.
T241 28024-28167 Sentence denotes Gingerol is stabilized by hydrogen bond, hydrophobic and van der Waals interactions in the binding pocket of the SARS-Cov-2 Mpro (Figure 4(d)).
T242 28168-28238 Sentence denotes VAL303 is interacting through hydrogen bond interaction with Gingerol.
T243 28239-28438 Sentence denotes The residues LYS12 and THR304 are involved in carbon-hydrogen bond interactions while MET6, ALA7, PHE8, GLN127, TYR154, ASP295 and ARG298 are associated with van der Waals interactions with Gingerol.
T244 28439-28545 Sentence denotes The interaction of Gingerol with the residues PRO9 and ILE152 is stabilized through pi–alkyl interactions.
T245 28546-28729 Sentence denotes The lowest energy binding poses of the rest 26 molecules along with the ligand interaction diagram at the binding sites of the SARS-CoV-2 Mpro are provided in Supplementary Figure S4.
T246 28730-28739 Sentence denotes Figure 4.
T247 28741-28882 Sentence denotes Lowest energy docked pose of (a) Piperine, (b) Capsaicin, (c) Carvone and (d) Gingerol with SARS-CoV-2 Mpro and their 2D interaction diagram.
T248 28883-28937 Sentence denotes The colour codes represent the nature of interactions.
T249 28939-28943 Sentence denotes 3.6.
T250 28945-28985 Sentence denotes Molecular dynamics (MD) simulation study
T251 28986-29164 Sentence denotes The MD simulation is one of the proven in-silico methods for the determination of protein–ligand dynamics concerning a high temporal resolution of nanosecond or picosecond order.
T252 29165-29310 Sentence denotes Here the docked poses of RBD Spro and Mpro with Piperine were used for a 100 ns MD simulation to analyse the stability of these docked compounds.
T253 29312-29318 Sentence denotes 3.6.1.
T254 29320-29353 Sentence denotes Root mean square deviation (RMSD)
T255 29354-29455 Sentence denotes The RMSD values from MD simulation provide information about structural and conformational stability.
T256 29456-29549 Sentence denotes Figure 5 represents the backbone RMSD data of viral proteins and their complex with Piperine.
T257 29550-29659 Sentence denotes From the plot, it is observed that both the simulations have less fluctuation throughout the simulation time.
T258 29660-29845 Sentence denotes The average RMSD values of RBD Spro, RBD Spro-Piperine, Mpro and Mpro-Piperine are calculated as 0.143 ± 0.025 nm, 0.130 ± 0.018 nm, 0.212 ± 0.041 nm and 0.203 ± 0.028 nm, respectively.
T259 29846-29998 Sentence denotes The average RMSD values of the Piperine bound proteins as compared to only proteins are found to be less representing to their conformational stability.
T260 29999-30184 Sentence denotes Both the simulations are attained equilibrium within 0.3 nm, which is also a measure of the systems’ stability during the simulation (Al-Shabib et al., 2018, 2020; Millan et al., 2018).
T261 30185-30194 Sentence denotes Figure 5.
T262 30196-30324 Sentence denotes Root mean square deviation plots of (a) RBD Spro (black) and RBD Spro-Piperine (red); (b) Mpro (black) and Mpro-Piperine (blue).
T263 30326-30332 Sentence denotes 3.6.2.
T264 30334-30369 Sentence denotes Root mean square fluctuation (RMSF)
T265 30370-30551 Sentence denotes The conformational fluctuations of the proteins RBD Spro and Mpro were analysed by observing the residual changes that resulted due to the interaction of Piperine with the proteins.
T266 30552-30659 Sentence denotes The RMSF plots of the Cα atoms of the viral proteins and their complex with Piperine are shown in Figure 6.
T267 30660-30865 Sentence denotes From the analysis, it is found that RBD Spro, RBD Spro-Piperine, Mpro and Mpro-Piperine have the average RMSF values 0.099 ± 0.060 nm, 0.097 ± 0.051 nm, 0.119 ± 0.077 nm and 0.120 ± 0.077 nm, respectively.
T268 30866-31065 Sentence denotes It is observed that RBD Spro-Piperine (Figure 6(a)) and Mpro-Piperine (Figure 6(b)) show similar fluctuations as compared to only RBD Spro and Mpro, which implies to the stability of these compounds.
T269 31066-31168 Sentence denotes In addition to that, a majority of the protein residues are found to be stabilized within RMSF 0.3 nm.
T270 31169-31280 Sentence denotes The decrease in fluctuations of Piperine bound to RBD Spro also suggests for the active binding of Piperine (A.
T271 31281-31312 Sentence denotes Kumar, Choudhir, et al., 2020).
T272 31313-31322 Sentence denotes Figure 6.
T273 31324-31466 Sentence denotes Root mean square fluctuation plots of Cα-atoms of (a) RBD Spro (black) and RBD Spro-Piperine (red); (b) Mpro (black) and Mpro-Piperine (blue).
T274 31468-31474 Sentence denotes 3.6.3.
T275 31476-31499 Sentence denotes Radius of gyration (Rg)
T276 31500-31616 Sentence denotes The root mean square distance between an object and the centre of gravity is defined as the radius of gyration (Rg).
T277 31617-31841 Sentence denotes The radius of gyration is a measure of the compactness of the protein structure, where higher Rg value is referred to as a less compact structure, and low Rg value is inferred as high compactness that implies more stability.
T278 31842-32020 Sentence denotes The measured average Rg values of RBD Spro, RBD Spro-Piperine, Mpro and Mpro-Piperine are 1.829 ± 0.008 nm, 1.833 ± 0.010 nm, 2.233 ± 0.012 nm and 2.238 ± 0.013 nm, respectively.
T279 32021-32273 Sentence denotes From Figure 7(a,b), it is observed that there is a little enhancement in the Rg values of RBD Spro-Piperin, and Mpro-Piperine as compared to RBD Spro and Mpro, which implies to the gain in compactness of the protein structures upon binding to Piperine.
T280 32274-32283 Sentence denotes Figure 7.
T281 32285-32519 Sentence denotes Radius of gyration plots of (a) RBD Spro (black) and RBD Spro-Piperine (red); (b) Mpro (black) and Mpro-Piperine (blue); (c) Intermolecular hydrogen bonds formed between RBD Spro-Piperine and Mpro-Piperine during 100 ns MD simulation.
T282 32521-32527 Sentence denotes 3.6.4.
T283 32529-32553 Sentence denotes Number of hydrogen bonds
T284 32554-32693 Sentence denotes The number of hydrogen bonds formed between the protein–ligand complex is the measure of the binding strength of the ligand to the protein.
T285 32694-32837 Sentence denotes The RBD Spro (red) and Mpro (blue) bound to Piperine have a constant number of 1–2 hydrogen bonds throughout the simulation time (Figure 7(c)).
T286 32838-32964 Sentence denotes There is a maximum number of 3 and 4 hydrogen bonds observed in the case of RBD Spro-Piperine and Mpro-Piperine, respectively.
T287 32965-33180 Sentence denotes The number of hydrogen bonds fluctuates throughout the simulation time for both RBD Spro-Piperine and Mpro-Piperine, which suggests for conformational changes in the binding site of the ligand during the simulation.
T288 33181-33299 Sentence denotes The observation from hydrogen bond analysis indicates that the complexes are stable for the performed simulation time.
T289 33301-33307 Sentence denotes 3.6.5.
T290 33309-33327 Sentence denotes Interaction energy
T291 33328-33424 Sentence denotes The interaction energy is the measure of the interaction strength of the protein–ligand complex.
T292 33425-33567 Sentence denotes In order to validate the results of molecular docking studies, the analysis of the interaction free energies from MD simulation was performed.
T293 33568-33690 Sentence denotes The average interaction energy takes the contribution from the average short-range Lennard-Jones and van der Waals energy.
T294 33691-33847 Sentence denotes The average interaction energies of RBD Spro-Piperine and Mpro-Piperine are found to be − 41.401 ± 17.843 kJ/mol and −143.162 ± 23.043 kJ/mol, respectively.
T295 33848-34082 Sentence denotes These interaction energy values suggest that Piperine binds to the RBD Spro and Mpro with good affinity and hence supports the docking results, which in turn helps for the favourable use of Piperine as a drug candidate for SARS-CoV-2.
T296 34084-34090 Sentence denotes 3.6.6.
T297 34092-34130 Sentence denotes Solvent accessible surface area (SASA)
T298 34131-34223 Sentence denotes SASA is a measure of the receptor exposure to the solvent environment during the simulation.
T299 34224-34362 Sentence denotes The hydrophobic residues that got exposed to the solvent environment upon binding with the ligand molecules contribute to the SASA values.
T300 34363-34454 Sentence denotes The plot of the SASA for the proteins and their ligand-bound form is presented in Figure 8.
T301 34455-34652 Sentence denotes The analysed average SASA values for the RBD Spro, RBD Spro-Piperine, Mpro and Mpro-Piperine are 106.976 ± 1.602 nm2, 107.235 ± 1.667 nm2, 150.698 ± 2.565 nm2 and 151.022 ± 2.207 nm2, respectively.
T302 34653-34827 Sentence denotes There is no significant change observed for the averaged SASA values of the complex as compared to only protein suggesting their stability after binding to the drug molecule.
T303 34828-34837 Sentence denotes Figure 8.
T304 34839-34979 Sentence denotes Solvent accessible surface area (SASA) plots of (a) RBD Spro (black) and RBD Spro-Piperine (red); (b) Mpro (black) and Mpro-Piperine (blue).
T305 34981-34987 Sentence denotes 3.6.7.
T306 34989-35024 Sentence denotes MMPBSA binding free energy analysis
T307 35025-35123 Sentence denotes MD simulation can also be used to calculate the binding free energy of the protein–ligand complex.
T308 35124-35270 Sentence denotes The binding free energy is the measure of the stability of the system in turns of consistency of nonbonded interactions throughout the simulation.
T309 35271-35378 Sentence denotes The binding free energy was calculated by using MMPBSA method by taking 2000 snapshots from the trajectory.
T310 35379-35529 Sentence denotes The computed value of binding free energy for RBD Spro-Piperine is found to be −5.533 ± 0.839 kJ/mol, and for Mpro-Piperine is −37.971 ± 0.271 kJ/mol.
T311 35530-35647 Sentence denotes It is observed that for both RBD Spro and Mpro, van der Waals energy plays a crucial role in the interaction process.
T312 35648-35773 Sentence denotes The van der Waals energy, electrostatic energy and non-polar energy are contributed actively to the total interaction energy.
T313 35774-35861 Sentence denotes In contrast, polar energy has a positive contribution to the whole interaction process.
T314 35862-36015 Sentence denotes The observed data indicate that the van der Waals, electrostatic and non-polar interactions combinedly contribute to the stability of both the compounds.
T315 36016-36166 Sentence denotes The contribution from different interactions to the binding free energy for RBD Spro-Piperine and Mpro-Piperine is provided in Supplementary Table S2.
T316 36167-36175 Sentence denotes Table 2.
T317 36177-36312 Sentence denotes Lowest energy binding affinity of Piperine and few of the currently used drugs for SARS-CoV-2 as obtained from molecular docking study.
T318 36313-36350 Sentence denotes Molecule Binding affinity (kcal/mol)
T319 36351-36365 Sentence denotes RBD Spro Mpro
T320 36366-36386 Sentence denotes Piperine –6.4 –7.3
T321 36387-36410 Sentence denotes Chloroquine –5.0 –4.9
T322 36411-36434 Sentence denotes Favipiravir –5.3 –5.6
T323 36435-36465 Sentence denotes Hydroxychloroquine –4.8 –6.0
T324 36466-36489 Sentence denotes Oseltamivir –5.1 –5.5
T325 36490-36512 Sentence denotes Remdesivir –6.1 –7.2
T326 36513-36534 Sentence denotes Ribavirin –5.6 –6.1
T327 36536-36542 Sentence denotes 3.6.8.
T328 36544-36578 Sentence denotes Principal component analysis (PCA)
T329 36579-36668 Sentence denotes The PCA is an essential technique to monitor the conformational dynamics of biomolecules.
T330 36669-36788 Sentence denotes It is useful in determining the concerted motion of protein as well as protein–ligand complex from the MD trajectories.
T331 36789-36958 Sentence denotes The diagonalization of the covariance matrix of backbone atoms of the proteins and ligand-bound form were considered for the principal components PC1 and PC2 (Figure 9).
T332 36959-37135 Sentence denotes From Figure 9(a,b), it is observed that both the Spro-Piperine and Mpro-Piperine are less flexible as compared to unbound proteins since they covered less conformational space.
T333 37136-37229 Sentence denotes It concludes that the ligand-bound forms are more stable as compared to the unbound proteins.
T334 37230-37239 Sentence denotes Figure 9.
T335 37241-37365 Sentence denotes Principal component analysis of (a) RBD Spro (black), RBD Spro-Piperine (red) and (b) Mpro (black) and Mpro-Piperine (blue).
T336 37366-37467 Sentence denotes Free energy landscape plot of (c) RBD Spro, (d) RBD Spro-Piperine and (e) Mpro and (f) Mpro-Piperine.
T337 37468-37683 Sentence denotes The principal components obtained were used as the reaction coordinates to find the Gibbs free energy landscape (Figure 9) to visualize the energy minima of the unbound protein as well as the protein–ligand complex.
T338 37684-37899 Sentence denotes From Figure 9(c–f), it is observed that both the ligand-bound proteins have less Gibbs-free energy values than the unbound proteins indicating their stability and energetically favourable conformational transitions.
T339 37900-38147 Sentence denotes The shape and size of the minimum energy area (blue colour) in case of RBD Spro-Piperine and Mpro-Piperine are more as compared to the unbound proteins RBD Spro and Mpro, which suggests the ligand-bound forms are thermodynamically more favourable.
T340 38148-38304 Sentence denotes The comprehensive study reveals that Piperine forms a stable complex with RBD Spro and Mpro and can be considered as an active inhibitor against SARS-CoV-2.
T341 38305-38489 Sentence denotes From the docking results, it is observed that the Piperine molecule is the best candidate for the inhibition of the RBD Spro and the Mpro of SARS-CoV-2 among the selected 30 molecules.
T342 38490-38778 Sentence denotes To observe the effectiveness of Piperine over currently used drugs, we carried out the docking study of a few drug molecules such as chloroquine, favipiravir, hydroxychloroquine, oseltamivir, remdesivir and ribavirin using the same docking protocol as followed for the 30 spice molecules.
T343 38779-38899 Sentence denotes From the docking score, it is found that Piperine performed better as compared to the currently used drugs stated above.
T344 38900-39094 Sentence denotes The lowest energy pose of a few presently used drugs with their 2D interaction diagram is provided in Supplementary Figures S5 and S6 corresponding to SARS-CoV-2 Mpro and RBD Spro, respectively.
T345 39095-39213 Sentence denotes A comparison of the lowest energy dock scores of these drug molecules along with Piperine is also provided in Table 2.
T346 39214-39339 Sentence denotes The MD simulation results reveal that Piperine actively inhibits both the RBD Spro and Mpro by binding to their active sites.
T347 39340-39442 Sentence denotes Piperine binds on the active site of the RBD Spro with those residues by which it interacts with ACE2.
T348 39443-39553 Sentence denotes So, the binding of Piperine on that site may potentially cease the interaction tendency of RBD Spro with ACE2.
T349 39554-39658 Sentence denotes Similarly, the interaction of Piperine on the active site of the Mpro may inhibit its viral replication.
T350 39659-39879 Sentence denotes From the docking and MD results, we conclude that Piperine forms a very stable complex with RBD Spro and Mpro and shows better affinity as compared to the currently used drugs that are mentioned above against SARS-CoV-2.
T351 39881-39883 Sentence denotes 4.
T352 39885-39895 Sentence denotes Conclusion
T353 39896-40123 Sentence denotes This study used molecular docking and MD simulation as potential tools to monitor the inhibitory efficiency of natural spice molecules against SARS-CoV-2, which emerged as a global threat to millions of people across the globe.
T354 40124-40281 Sentence denotes It is observed that all the proposed spice molecules qualified the ADME test with their suitable pharmacokinetic properties to be useful as a drug candidate.
T355 40282-40450 Sentence denotes The docking study is revealed that all the molecules actively take part in binding to the SARS-CoV-2 RBD Spro and Mpro with their low or high value of binding affinity.
T356 40451-40591 Sentence denotes This binding of these molecules will help to inhibit the replication of the viral proteins with specific hindrances upon their mutarotation.
T357 40592-40751 Sentence denotes For both the viral targets, Piperine performed well with its highest binding affinity of −6.4 and −7.3 kcal/mol for SARS-CoV-2 RBD Spro and Mpro, respectively.
T358 40752-40848 Sentence denotes Besides, Piperine is also found more effective as compared to a few of the currently used drugs.
T359 40849-40959 Sentence denotes The MD simulation study is supported for the stable interaction of Piperine with SARS-Cov-2 RBD Spro and Mpro.
T360 40960-41105 Sentence denotes The PCA and binding free energy results also suggest for the active participation of Piperine in stable complex formation with RBD Spro and MPro.
T361 41106-41196 Sentence denotes Hence, the study proposes Piperine as an active molecule for the inhibition of SARS-CoV-2.
T362 41197-41325 Sentence denotes Since this study is performed computationally, it requires wet-lab experiments in-vitroas well as in-vivofor further validation.
T363 41327-41349 Sentence denotes Supplementary Material
T364 41350-41371 Sentence denotes Supplemental Material
T365 41372-41408 Sentence denotes Click here for additional data file.
T366 41410-41426 Sentence denotes Acknowledgements
T367 41427-41614 Sentence denotes The authors are thankful to the Ministry of Human Resource Development (MHRD), New Delhi, for financial assistance (MHRD/(FDC)/2015–2016/438/INST) to establish the computational facility.
T368 41615-41738 Sentence denotes We are also extremely grateful to Dr. Anand Kant Das, New York University, Abu Dhabi, for a fruitful scientific discussion.
T369 41740-41760 Sentence denotes Disclosure statement
T370 41761-41805 Sentence denotes The authors declare no conflict of interest.
T371 41807-41820 Sentence denotes Abbreviations
T372 41821-41854 Sentence denotes COVID-19 coronavirus disease 2019
T373 41855-41913 Sentence denotes SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
T374 41914-41941 Sentence denotes RBD receptor-binding domain
T375 41942-41960 Sentence denotes Spro spike protein
T376 41961-41979 Sentence denotes Mpro main protease
T377 41980-42017 Sentence denotes MEP molecular electrostatic potential
T378 42018-42050 Sentence denotes PCA principal component analysis
T379 42051-42103 Sentence denotes ADME absorption, distribution, metabolism, excretion