key: cord-0898633-h1v6canl
authors: Allam, Ahmed E.; Amen, Yhiya; Ashour, Ahmed; Assaf, Hamdy K.; Hassan, Heba Ali; Abdel-Rahman, Islam M.; Sayed, Ahmed M.; Shimizu, Kuniyoshi
title: In silico study of natural compounds from sesame against COVID-19 by targeting M(pro), PL(pro) and RdRp
date: 2021-06-24
journal: RSC Adv
DOI: 10.1039/d1ra03937g
sha: 9648e67b91bcb1fcc6053e1f6721e29bed230038
doc_id: 898633
cord_uid: h1v6canl

Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads. Natural products as sesame were reported to exhibit potential to protect from COVID-19 disease. In our study, the total methanolic extract of Sesamum indicum L. seeds (sesame) were led to isolation of seven known compounds, five lignan; sesamin 1, sesamolin 2, pinoresinol 3, hydroxymatairesinol 6, spicatolignan 7, together with two simple phenolic compounds; ferulic acid 4 and vanillic acid 5. All isolated compounds were evaluated in silico against three important SARS-CoV-2 protein targets; main protease (M(pro)), papain-like protease (PL(pro)) and RNA-dependent RNA polymerase (RdRp) which possessed crucial role in replication and proliferation of the virus inside the human cell. The results revealed that compound 6 has the high affinity against the three main proteins, specially towards the SARS-CoV-2 M(pro) that exceeded the currently used SARS-CoV-2 M(pro) inhibitor darunavir as well as, exhibiting a similar binding energy at SARS CoV-2 PLpro when compared with the co-crystallized ligand. This activity continued to include the RdRp as it displayed a comparable docking score with remdesivir. Inferiorly, compounds 1 and 2 showed also similar triple inhibitory effect against the three main proteins while compound 7 exhibited a dual inhibitory effect against SARS CoV-2 PL(Pro) and RdRp. Further molecular dynamic simulation experiments were performed to validate these docking experiments and to calculate their binding free energies (ΔGs). Compounds 1, 2, 3, 6, and 7 showed comparable binding stability inside the active site of each enzyme with ΔG values ranged from −4.9 to −8.8 kcal mol(−1). All the compounds were investigated for their ADME and drug likeness properties, which showed acceptable ADME properties and obeying Lipinski's rule of five parameters. It can be concluded that the isolated compounds from sesame lignans could be an alternative source for the development of new natural leads against COVID-19.

COVID-19, a newly emerged respiratory disease, is a worldwide pandemic which could cause death. The symptoms of COVID-19 range from mild to moderate including fever, headaches, dry coughing, dyspnea, diarrhea, loss of taste, fatigue, viral pneumonia, acute respiratory distress, and hypoxia. In severe cases, COVID-19 patients require oxygen therapy and mechanical ventilation. 2 SARS-CoV-2 infection can activate innate and adaptive immune responses. However, uncontrolled inammatory innate responses and impaired adaptive immune responses may lead to harmful tissue damage, both locally and systemically. 2 Several antiviral drugs, including the nucleotide analogue remdesivir, are being actively tested; none has been specically approved for COVID-19. Along with vaccine development and approaches that target the viral block, treatment therapies that address the immunopathology of the contagion have become a major objective.

Sesame (Sesamum indicum L.) is one of the rst crops processed for oil production. It is edible seeds and has a rich source of protein, as well as, one of the earliest condiments. 3 Sesame seed contains about 50-60% of oil which is rich in different bioactive compounds including polyunsaturated fatty acids, tocopherol homologues, in addition to, lignans. 4 These bioactive constituents enhance the stability and keeping quality of sesame oil along with numerous health benets and have some important actions such as lowering cholesterol in humans, preventing high blood pressure and increasing vitamin E supplies in animals. 5 Moreover, antioxidant and anticarcinogenic activities of sesame seed have greatly increased its applications in health food products that assert for liver and heart protection and tumor prevention. 6 A folk method expressed that adding sesame oil into the nostrils can prevent the spread of SARS-CoV-2. To nd theoretical reasons to support this method for preventing viral infection with SARS-CoV-2, Fan et al. discussed from the perspective of colloid and interface science that sesame oil had a low surface tension and was incompatible with water. [7] [8] [9] Recently, the Indian government gave similar recommendations that instilling two drops of sesame oil in each nostril every morning to prevent the new coronavirus. 10 Sesame oil reported as having the ability to prevent the spread of SARS-CoV-2 due to the physical-chemical properties of sesame oil, such as low surface tension, high-boiling point, high viscosity, immiscible with water and antivirus activity. 9 Several drug discovery approaches like quantitative structureactivity relationship (QSAR), virtual screening (VS), articial intelligence and drug repositioning, are strongly required to help in discovering a treatment of the uncontrolled pandemic caused by SARSCoV-2. 11 Numerous molecular studies were addressed to gure out the active sites of the SARS-CoV-2. Main protease (M pro ). 12 Papain-like protease (PL pro ). 13 and RNA-dependent RNA polymerase (RdRp). 14 of SARS-CoV-2 are some of the decisive factors in the infectious route of the virus, they have been reported as important targets for therapeutic strategies.

Main protease (M pro ) is a crystal structure was mainly used to elucidate the mechanism of inhibition by ligand N3. [14] [15] [16] [17] [18] The recognition of the co-crystallized structure with inhibitor N3 (PDB 6LU7) interaction with human ACE2 (PDB 6M0J) provides a grasp of the active sites and the important amino acids that are responsible for the restraint of SARS-CoV-2. 19 Moreover, it is having a precious role in enzymatic activity leading to its posttranslational modication of replicase polyproteins.

Papain-like protease (PL pro ) is a cysteine protease, proteolytically cleaves the viral polyprotein precursors, pp1a and pp1ab, at three sites to produce non-structural proteins Nsp1, Nsp2, and Nsp3. 20 Hence, the two proteases M pro and PL pro are equally important in the transcription/replication of the virus and for novel discovery of antiviral drug design. 21 RNA-dependent RNA polymerase (RdRp), the core component of this complex is the catalytic subunit (Nsp12) of RdRp. 22 This enzyme plays a vital role in a complex form with Nsp7 and Nsp8, in the replication of the viral RNA. It is considered as a target of different antiviral drugs encompassing remdesivir especially in its triphosphate form. 23 Complex of Nsp12 with Nsp7, Nsp8 together with remdesivir triphosphate and a short RNA sequence have been crystallized (PDB 7BV2). This crystal structure was used to test the ability of the compounds isolated from sesame to be docked in the active site of RdRp, comparing with the position occupied by remdesivir triphosphate.

In the present study, the isolated compounds from sesame were investigated for the binding affinity with an in silico study against three important SARS-CoV-2 protein targets, main protease (M pro ), Papain-like protease (PL pro ) and RNA-dependent RNA polymerase (RdRp), to explore and development of drugs from natural food sources acting on pandemic COVID-19.

The total methanolic extract of Sesamum indicum L. seeds were subjected to repeated open column chromatography techniques to afford seven known compounds, sesamin 1, 24 sesamolin 2, 25 Fig. 1 Structure of the isolated compounds. pinoresinol 3, 26 ferulic acid 4, 27 vanillic acid 5, 28 hydroxymatairesinol 6. 29 which is rst isolated from the species Sesamum indicum L. Spicatolignan 7, which is rst isolated from the genus Sesamum, 30 Fig. 1 . The structures of known compounds were identied by comparison of their spectroscopic data with those reported in the literature.

The selected seven compounds were screened against the three important protein targets of SARS-CoV-2, i.e., M pro , PL pro and RdRp by performing molecular docking using the computational program MOE 2019.010.

The SARS-CoV-2 interacted rst with the transmembrane protein of the human host cell receptor ACE. 31 This process also internalizes the virus into the endosomes that allowed the virus to enter the human host cell. Thereaer, the RdRp facilitates the viral genome replication. 32 The 3CL pro and PL pro act as proteases in the process of proteolysis of the viral polyprotein into functional units. 33 Consequently, the M pro , PL pro , RdRp responsible for translation of the genetic materials of the virus along with the replication inside the host cell ending with the proliferation of the virus into human cells. Therefore, these three proteins of SARS-CoV-2 play a pivotal role in viral life cycle and were considered as the therapeutic protein targets for the molecular docking with the selected seven compounds.

2.2.1. Docking against M pro . The rst target is SARS-CoV-2 main protease (M pro ) represented as a 3C-like protease with Cys-His catalytic dyad which is responsible for the release of essential functioning peptides. M pro is considered as a promising target against SARS-CoV-2 due to its importance in the viral life cycle and because of the absence of human homologues. 34 The X-ray crystallographic structure of M pro complexed with N3 was obtained from the Protein Data Bank through the internet (http://www.rcsb.org/pdb/, code 6LU7). The substratebinding site is in a cle between domain I and II. A Michael acceptor inhibitor known as N3 was developed using computeraided drug design. N3 is tted inside the substrate-binding pocket of SARS-CoV-2 virus M pro showing asymmetric units containing only one polypeptide.

To validate our study, the ligand was re-docked with the active pocket. N3 showed interactions with receptor having HB formations with Thr 190, Glu 166, Gln 189, His 163, His 164 residues (Fig. 2 ). The docking algorithm was able to predict the co-crystalized ligand pose with low RMSD value of 1.2Å and binding affinity score of À8.45 kcal mol À1 (Fig. 2) . The docking scores of the seven compounds against M pro0 active site is summarized in Table 1 . Five compounds showed docking scores higher than À6.4 kcal mol À1 . Interestingly compound 6 (hydroxymatairesinol) showed binding energy score of À7.46 kcal mol À1 , which is higher than the docking score of the currently used M pro inhibitor darunavir (À7.1) kcal mol À1 . It showed hydrogen bonding (HB) interaction with Met165 and Ser144 via the phenolic hydroxyl groups in both rings as a HB donor and with Gly143 as a HB acceptor through the aliphatic hydroxyl group. Compound 1 (sesamine) got a docking score of À6.71 kcal mol À1 and exhibited good binding mode with important interactions with Gln 189:HB donor and Thr 190:HB donor as shown in Table 1 , similarly compound 2 (sesamolin) displayed the same key binding mode that resembles the binding mode in N3. Compound 7 (specatolignan) achieved an energy score of À6.74 kcal mol À1 forming HB binding via the carboxylic group entity with amino acid residues Glu 166 and Thr 190 as a HB donor and HB acceptor respectively. The order of docking scores was as follows: N3> 3 > darunavir > 2 > 6 > 1 > 4 > 5 > 7.

2.2.2. Docking against PL pro . The X-ray crystallographic structure of SARS CoV-2 papain-like protease (PDB 6WUU), was retrieved from the protein data bank a. Papain-like cysteine protease (PL pro , Nsp3) is essential for SARS-CoV-2 replication and represents a promising target for the development of antiviral drugs. 35 Despite huge research efforts on SARS-CoV-2 M pro inhibitors, proteomic and structural biology works on SARS-CoV-2 PL pro and its inhibitors are very few. Nevertheless, Rut and co-workers utilised HyCoSuL (Hybrid Combinatorial Substrate Library) to scrutinize substrate specicity of SARS-CoV-2 PL pro enzymes. 33 Two irreversible inhibitors namely VIR250 and VIR251 having high degree of PL pro selectivity over other proteases were identied. The same study reported their crystal structures bound to the enzyme's active site. Altogether, these crystal structures in complex with VIR250 (PDB 6WUU) provide a basic for rapid rational drug design against SARS-CoV-2 PL pro .

The designed ligands were docked into the active site of SARS CoV-2 papain-like protease. The results of the docking scores of the designed ligands and their RMSD values are reported in Table 2 .

Docking scores are comprised in the range À4.68 to À7.20 kcal mol À1 , 5 compounds possessed docking scores a S: the score of a compound placement inside the protein binding pocket. b RMSD_rene: the root-mean-squared-deviation (RMSD) between the predicted pose and those of the crystal one (aer and before renement process, respectively). a S: the score of a compound placement inside the protein binding pocket. b RMSD_rene: the root-mean-squared-deviation (RMSD) between the predicted pose and those of the crystal one (aer and before renement process, respectively).

above À6.4 kcal mol À1 ; compound 6 (hydroxymatairesinol) achieved a similar value of binding energy as the co-crystallized ligand VER 250 with S ¼ À7.2085 kcal mol À1 ; the 2D interactions shown in Fig. 3 and Table 3 , displayed HB binding mode with Met 208 and Asp 164 amino acid residues as H-donor while the binding with Arg166 as H-acceptor, followed by compound 7 with S value of À6.6183 kcal mol À1 also compound 1 and compound 3 revealed a comparable binding free energies with values À6.5524 and À6.5131 kcal mol À1 , respectively. 2.2.3. Docking against RdRp. SARS-CoV-2 is a member of a family of viruses that consists of a positive strand RNA, which mainly dependent on a multi subunit complex of viral nonstructural proteins (Nsp) (RNA-dependent RNA polymerase, RdRp), for their transcription and replication. The main subunit of this complex is the (Nsp 12), this catalytic subunit needed an activation through another two accessory subunits (Nsp7) and (Nsp8), this complex of Nsp12-Nsp7-Nsp8 have been determined, 35 so that the overall architecture of the RdRp complex was provided. As such, RdRp has been a subject of intensive structural biology efforts. Remdesivir is clinically used as a prodrug that gets converted to RTP (remdesivir triphosphate) which binds covalently to the mRNA strand and stops the mRNA transcription and replication of SARS-CoV-2. The residues Asp760 and Asp761 also interact with the remdesivir triphosphate via hydrogen bond interactions. Nsp12, complexed with Nsp7, Nsp8, remdesivir triphosphate and a short RNA sequence have been crystallized (PDB 7BV2). 25 . Redocking of remdesivir triphosphate for validation of the docking method resulted in a similar pose to the crystal structure and attained an energy score of À7.2069 kcal mol À1 with RMSD 1.0485, Fig. 4 . The investigated sesame compounds were docked at the same active site that occupied by the remdesivir in the complex of Nsp12-Nsp7-Nsp8 and the template RNA, from the docking results Table 4 , compound 6 achieved a binding energy score of À7.0179 kcal mol À1 that resembles the one obtained with the co crystallized ligand (remdesivir), the binding mode of the compound 6 showed a similarity with remdesivir in HB binding with nucleotide U10 as H-acceptor and as a H-donor with amino acid residue Asp760 both of the hydroxyl groups the alcoholic and the phenolic contributed in this interaction respectively. The binding with nucleotide U 20 was indicated as a type of H-Pi binding and with the residue Asp 623 as Pi-H interaction with the aromatic ring of the docked compounds, Table 5 . It's noteworthy that, compound 1 possessed a dock score of À7.348 kcal mol À1 exceeding the score attained with remdesivir but no interaction obtained with the receptor with this selected pose, compound 2 also revealed a comparable free energy score of À6.9807 kcal mol À1 and good stability inside the pocket site but with no fundamental interactions.

Drug-likeness is a smooth balance among molecular properties affecting pharmacodynamics and pharmacokinetics of molecules, these molecular properties such as membrane permeability and bioavailability are always connected to some basic molecular descriptors such as log P (partition coefficient), molecular weight (MW), topological polar surface area (TPSA), or hydrogen bond acceptors and donors count in a molecule. BOILED-egg diagram showing the possibility of absorption and penetration of inhibitors in the GI attract and brain using a S: the score of a compound placement inside the protein binding pocket. b RMSD_rene: the root-mean-squared-deviation (RMSD) between the predicted pose and those of the crystal one (aer and before renement process, respectively).

WLOGP and TPSA parameters, the basis of Egan's BOILED-Egg rule threshold values (WLOGP # 5.88 and TPSA # 131.6).

Results of ADME prediction revealed that all investigated compounds exhibited acceptable ADME properties, compounds 2, 5 and 6 showed oral absorption, which is an important criterion for a drug that is intended for mass treatment. In addition, compounds 1, 3 and 4 can cross the blood brain barrier though within acceptable limits. Binding to P-glycoprotein (PGP+) was also studied and plotted, Fig. 5 and Table 6 .

All the investigated compounds obeying Lipinski's rule of ve parameters. 36 They have H-bond acceptor less than 10 and donor centres less than 5, these atoms favour H-bond formations and consequently develop water solubility. The obtained log P values and bioactivity scores (F > zero) revealed that they have a substantial bioavailability and cross the cell membrane efficiently. 37 Also, all the compounds showed acceptable MW and convenient TPSA values. Table 7 .

Compound 6 satises all parameters of the Lipinski's rule, and complies to the BOILED-Egg approach showing no brain absorption and good GI tract absorption, which renders it a more suitable potential orally active drug and therapeutic inhibitor of SARS CoV-2 to be tested in clinical trials.

The structure of the SARS-CoV-2 RdRp in complex with a 50base template-primer RNA and remdesivir. The doublestranded RNA template is inserted into the central channel of the RdRp where remdesivir, which considered as nucleoside analogue, is incorporated into the primer strand at the rst replicated base pair and terminates chain elongation. 38 Here the interaction between compound 6 methylene group and the uracil nucleotide 20 of the RNA in the form of H-Pi interaction resemble an interaction of the ligand remdesivir with it, which contribute with the other interactions either with the amino acid residues or the nucleotide in inhibition of the RdRp complex and stops the mRNA transcription and replication of SARS-CoV-2.

Further validation of the docking results was achieved via molecular dynamic simulations (MDS). Docking poses of the compounds with docking scores <À6 were subjected to a number of 50 ns MDS experiments to study their binding stabilities and to calculate their binding free energies (DGs).

Compounds 1, 2, 3, 6 and 7 got docking scores <À6 kcal mol À1 upon docking against M pro , PL pro and RdRp. As shown in Table 8 and Fig. 5 , all of these compounds achieved comparable binding stability during the course of MDS.

Hydroxymatairesinol 6 was showed the least uctuations and deviations from its starting binding pose with M pro (RMSD $ 2.8Å), and hence, the lowest DG. Sesamin 1 show an average RMSD (2.7Å) similar to that of hydroxymatairesinol 6 until 29.6 ns, when its deviation started to increase gradually to end with 5.5Å. Similarly, sesamolin 2 showed stable RMSD around 2.9Å until 11.6 ns, when its RMSD suddenly increased to reach 5.6Å and became equilibrated around this point until the end of MDS with low uctuations. Spicatolignan 7 showed lowest RMSD (2.1Å) until 15 ns. Starting from this point its uctuations a round RMSD ¼ 3.9Å increased dramatically. Pinoresinol 3 showed the highst uctuations and deviations inside the M pro0 s active site ending up the MSD with and average RMSD of 7.7Å and DG ¼ À5.2 kcal mol À1 .

In case of PL pro , compounds 2, 3, 6 and 7 showed convergent steady binding stability with average RMSDs ranged from 2.2 to 6.2Å showing minimal uctuations (Table 8 and Fig. 5 ). Sesamin 1 was signicantly less stable, where its RMSD was increasing gradually to reach 10.3Å at 18.4 ns, and then became uctuating around this point until the end of MDS.

Finally, binding stabilities of these compounds with RdRp's binding site were comparable showing relatively high uctuations and RMSDs ($5.1Å), except for sesamin and sinoresinol (1 and 3) that were signicantly more stable and steady (average RMSD ¼ 2.5Å) ( Table 8 and Fig. 5) , and got the lowest DG values (À8.4, À8.8 kcal mol À1 , respectively).

From the previous reports on the molecular modelling-based screening of SARS CoV-2's molecular targets, particularly, M pro , it can be concluded that: (i) ensemble docking protocols give more accurate results than simple ones as the former takes into account the active site's exibility. 39 (ii) Docking results should be validated by at least 50 ns of MDS as some times compounds with good docking scores did not grantee stable binding. [40] [41] [42] (iii) Compounds that can achieve DG of À7 kcal mol À1 of lower have high potential to be active in vitro. [43] [44] [45] (iv) Compounds with good scores and binding stability should also have good druglike properties to be active in vitro. [46] [47] [48] Pi-Pi 3.83 0 a S: the score of a compound placement inside the protein binding pocket.

Silica gel was purchased from Wako (Osaka, Japan). Thin-layer chromatography (TLC) silica gel G 60 F 254 and reversed phase preparative TLC were purchased from Merck (Darmstadt, Germany). All other ingredients used were of the highest grade available. The 1 H, 13 C-NMR and 2D spectra of the isolated compounds were recorded using a Bruker DRX 600 NMR spectrometer (Bruker Daltonics, Billerica, MA).

5 kg of the fresh materials were freeze-dried and milled below 1 mm. Then, extracts were prepared by shaking (200 rpm) with solvent (methanol) at room temperature for 48 h to afford 59 g methanol extract. The extracted solution was ltered and evaporated using ADVANTEC no. 2 lter paper (Toyo Roshi Kaisha, Ltd., Tokyo).

The methanol extract was suspended in distilled water and fractionated using liquid-liquid partition to afford n-hexane fraction (12 g), ethyl acetate fraction (17 g) and the remaining aqueous fraction (5 g). The n-hexane fraction was subfractionated on a silica gel column using n-hexane-ethyl acetate gradient elution (100%, 80% and 70%). The sub fractions eluted by 70% n-hexane:ethyl acetate (70-30) was crystallized to give some needles crystals, which washed with MeOH The ethyl acetate fraction (17 g) was sub-fractionated on a silica gel column using n-hexane-ethyl acetate gradient elution (70%, 60%, 40% and 100%). The sub fractions eluted by n-hexaneethyl acetate 40% (70 : 30) resulted in compound 2 (200 mg). The sub fractions eluted by n-hexane-ethyl acetate 40% (40 : 60) was subjected to reversed phase preparative TLC using 30% water in MeOH which resulted in compound 3 (15 mg), compound 4 (2.4 mg) and compound 5 (1.6 mg). The sub fractions eluted by 100% ethyl acetate was crystallized to give some needles crystals, which washed with MeOH several times, then TLC was performed for checking purity to afford compound 6 (1.6 mg). The remaining sub fractions which were eluted by 100% ethyl acetate was subjected to sub-column using n-hexane : ethyl acetate in gradient manner to afford compound 7 (3.8 mg). The structure of all compounds was elucidated by 1D and 2D NMR spectroscopy, including 1 H, 13 C, HSQC and HMBC experiments the ESI. †

The X-ray crystallographic structure of protein targets of SARS-CoV-2 M pro (3CL pro ), PL pro , and RdRp complexed with their ligands was obtained from the Protein Data Bank through the internet (http://www.rcsb.org/pdb/, code 6LU7, 6WUU and 7BV2). All molecular modelling calculations and docking studies were carried out using 'Molecular Operating Environment 2019.0102' soware (MOE). The preparation of the protein included the removal of water molecules and uninvolved ligands then by using the quick preparation tool in MOE with applying the default options. Docking of the conformation database of the target compounds was done aer preparation of the enzyme. The following methodology was generally applied: the enzyme active site was located by the site nder tool, and the docking tool was initiated. The program specications were adjusted to ligand atoms as the docking site, alpha triangle as the placement methodology to be used and the post placement renement were adjusted to make the receptor rigid. The scoring methodology London dG is used and was adjusted to its default values. The MDB le of the ligand to be docked was loaded and dock calculations were run automatically. Receptor- ligand interactions of the complexes were examined in 2D and 3D styles the poses that showed best ligand-enzyme interactions were selected and stored for energy calculations. The selection of poses was done according to their better obtained binding scores and RMSD rene values, especially most of them achieved very close binding modes compared to the native ligand. The obtained scores, RMSD rene values, and interactions with binding pocket site of the enzymes are discussed.

Drug-likeness properties (Lipinski rule or rule of ve) and Physicochemical properties (BOILED-Egg diagram or ADME prediction), 49, 50 were calculated by the free access website of the predictor Swiss ADME (http://www.swissadme.ch/).

Molecular dynamic simulations (MDS) for the generated ligandenzyme complexes were performed using the Nanoscale Molecular Dynamics (NAMD) 2.6 soware, 51 applying the CHARMM27 force eld. 52 Hydrogen atoms were added to the protein structures using the psfgen plugin included in the Visual Molecular Dynamic (VMD) 1.9 soware. 53 Aerward, the whole generated systems were solvated using water molecules (TIP3P) and 0.15 M NaCl. At rst, the total energy of the generated systems was minimized and gradually heated to reach 300 K and equilibrated for 200 seconds. Subsequently, the MDS was continued for 50 ns, and the trajectory was stored every 0.1 ns and further analyzed with the VMD 1.9 soware. The MDS output was sampled every 0.1 ns to calculate the root mean square deviation (RMSD). The parameters of compound 4 were prepared using the online soware the VMD Force Field Toolkit (ffTK). 53 Binding free energies (DG) were calculated using the free energy perturbation (FEP) method (Jo et al. 2013 ). The web-based soware Absolute Ligand Binder 54 was used to generate the input les for NAMD soware which was performed the simulations required for DGs calculations.

The isolated compounds from sesame seeds, particularly compounds 1, 2, 3, 6, and 7, were found to exhibit considerable binding affinity with three key SARS CoV's proteins; M pro , PL pro and RdRp. This study pointed out the importance of using sesame as a source of naturally occurring compounds isolated from food sources in alleviating SARS-CoV-2, and hence an advice of using sesame seed as a part of food for COVID-19 patients. Additionally, it will help us to afford semisynthetic new scaffold with potential activity against this disease.

We declare that we have no conict of interest.

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The authors would like to acknowledge OpenEye scientic soware for providing the academic license. In addition, we acknowledge the Research and Education Support Center of the faculty of Agriculture, Kyushu University for supporting facilities for NMR and mass analysis.