key: cord-0784168-py5d5dsy authors: Khan, Suliman; Hussain, Arif; Vahdani, Yasaman; Kooshki, Hamideh; Mahmud Hussen, Bashdar; Haghighat, Setareh; Fatih Rasul, Mohammed; Jamal Hidayat, Hazha; Hasan, Anwarul; Edis, Zehra; Haj Bloukh, Samir; Kasravi, Shahab; Mahdi Nejadi Babadaei, Mohammad; Sharifi, Majid; Bai, Qian; Liu, Jianbo; Hu, Bowen; Akhtari, Keivan; Falahati, Mojtaba title: Exploring the interaction of quercetin-3-O-sophoroside with SARS-CoV-2 main proteins by theoretical studies: a probable prelude to control some variants of coronavirus including Delta date: 2021-07-28 journal: Arabian Journal of Chemistry DOI: 10.1016/j.arabjc.2021.103353 sha: 62966f28760c8d9adcdc4ebaeffe97308b81edae doc_id: 784168 cord_uid: py5d5dsy The aim of this study was to investigate the mechanism of interaction between quercetin-3-O-sophoroside and different SARS-CoV-2's proteins which can bring some useful details about the control of different variants of coronavirus including the recent case, Delta. The chemical structure of the quercetin-3-O-sophoroside was first optimized. Docking studies were performed by CoV disease-2019 (COVID-19) Docking Server. Afterwards, the molecular dynamic study was done using High Throughput Molecular Dynamics (HTMD) tool. The results showed a remarkable stability of the quercetin-3-O-sophoroside based on the calculated parameters. Docking outcomes revealed that the highest affinity of quercetin-3-O-sophoroside was related to the RdRp with RNA. Molecular dynamic studies showed that the target E protein tends to be destabilized in the presence of quercetin-3-O- sophoroside. Based on these results, quercetin-3-O- sophoroside can show promising inhibitory effects on the binding site of the different receptors and may be considered as effective inhibitor of the entry and proliferation of the SARS-CoV-2 and its different variants. Finally, it should be noted, although this paper does not directly deal with the exploring the interaction of main proteins of SARS-CoV-2 Delta variant with quercetin-3-O-sophoroside, at the time of writing, no direct theoretical investigation was reported on the interaction of ligands with the main proteins of Delta variant and the present data may provide useful information for designing some theoretical studies in the future for studying the control of SARS-CoV-2 variants due to possible structural similarity between proteins of different variants. Given the unique characteristics of the genetic material of coronaviruses (CoV), as well as the mechanism of their proliferation, the emergence of the severe acute respiratory syndrome CoV 2 (SARS-CoV-2) has not been unexpected for virologists (1) . Among these special features, the high genetic recombination rate of this virus has been led to the emergence of new and unknown strains (2) . The reason for this high recombinant frequency can be attributed to the very long genetic material of the virus compared to other viruses, the complex proliferation, and ultimately to the wide host range of these viruses in humans and animals (1) (2) (3) . In order to treat this virus, in addition to sufficient knowledge of this invasive and contagious virus (4, 5) , it is necessary for different countries to make correct and timely control decisions to take personal protective and hygienic measures (6, 7) . Due to severe tissue damage caused by SARS-CoV and middle east respiratory syndrome (MERS-CoV) infection, the mortality rate in infected patients requiring mechanical ventilation (artificial respiration) has been very serious (8, 9) . To date, there is no specific antiviral drug for the treatment of CoV (10, 11) , and the main solutions are based on supportive care, such as maintaining vital signs, regulating oxygen and blood pressure, and reducing side effects such as secondary infections or organ failure (12) (13) (14) . Based on the previous studies, a combination of protease inhibitors, lopinavir and ritonavir drugs has been shown to significantly improve the condition of COVID-19 patients (15) (16) (17) . The results of in vitro and in vivo studies show that a combination of lopinavir, ritonavir, and interferon β may be effective against MERS infection (18) . Recent studies have shown that viral proteins may be potential models for the design of new antiviral drugs to prevent the proliferation of SARS-CoV-2 and possible different variants (19) (20) (21) . The computational methods are widely used in the discovery, design, and optimization of potential compounds based on their structure, in which small molecules are docked into the structure of the target macromolecules and rated for their binding at the target site (22, 23) . The study of SARS-CoV-2 inhibitors to develop an effective drug to reduce mortality in COVID-19 patients has been a new topic in recent years (22) (23) (24) (25) . At present, the lack of appropriate methods to identify inhibitors' mechanism of action on SARS-CoV-2 function and maybe different variants, including Delta and the relationship between their chemical structure and antiviral effect encourages us to further examine their inhibitory effects against COVID-19 (26, 27) . Software and computational methods of drug design have been a new approach that their emergence and generality have been accompanied by advances in computing power over decades (26, 27) . These methods are used in conjunction with biological experiments to establish a relationship between the structure and activity of pharmaceutical compounds, the discovery of new compounds, the prediction of the biological activities of designed compounds, and the understanding of biochemical reactions and relative processes (28, 29) . In addition, these methods can be used to predict how the designed compounds bind to the target protein, evaluate the energy difference between different compound conformers, and explain the mechanisms of reaction, effect of different groups, decompositions in the chemical structure of compounds, and their performance (26) (27) (28) (29) . Quercetin-3-O-sophoroside as a major member of quercetin glucoside group is a well-acknowledged anti-inflammatory, anti-oxidant and anti-cancer edible compound (30) . Broccoli, and Poacynum hendersonii leaves have a high content of quercetin glucosides (30, 31) . Lee et al. [a] studied the inhibitory activity of quercetin-3-O-sophoroside against H1N1, H3N2, and H5N1 viruses. They suggested that the size of sugar moiety on quercetin-3-sophoroside and other flavonoids can affect the antiviral effect of these compounds. Hollman et al., (33) studied the catabolism of quercetin-3-O-sophoroside in the small intestine and likely during this process the sugar moiety is removed (34) . Since in this study the molecule has been studied in its intact form, non-oral methods should be prescribed in its possible medical use for the treatment of viral disease. Accessibility of the target protein and lack of closely related host cell counterparts which improve the inhibitory potency and fewer off-target effects against host proteins, are two important aspects in selecting favorable receptors among a wide variety of target proteins. Therefore, in this study, in order to identify the exact mechanism of quercetin-3-O-sophoroside performance and identify the amino acid residues involved in this process and the optimal energy of quercetin-3-O-sophoroside upon interaction with different SARS-CoV-2's proteins including, E protein (ion channel), helicase ADP site, helicase NCB site, main Protease, N protein NCB site, Nsp14 (ExoN), Nsp14 (N7-MTase), Nsp15 (endoribonuclease), Nsp16 (2'-O-MTase), papain-like protease, RdRp with RNA, and RdRp without RNA, molecular docking and molecular dynamic studies were done. This information may bring also some potential information about the control of and SARS-CoV-2 and possible variants. The quercetin-3-O-sophoroside molecule geometry optimization was carried out using the PM3 semiempirical method and a single point energy calculation was performed using Becke3-Parameter hybrid function which combined with the Lee-Yang-Parr correlation functional, abbreviated as B3LYP (35, 36) with the standard 6-31G(d,p) basis both implemented in the GAUSSIAN98W suite of programs (37). In order to investigate the affinity of quercetin-3-O-sophoroside toward covid-19 virus's receptors molecular docking calculations were carried out using COVID-19 Docking Server (38) . We used all proteins provided by this server, which uses the JSMol (http://jmol.sourceforge.net/) for molecular visualization, where the plots of complex configurations were extracted from this page. In order to study the adsorption effects of quercetin-3-O-sophoroside on target proteins, E protein was selected as the receptor model. The molecular dynamics calculation was performed using HTMD software (39) . The GAFF2 method (40) was employed for parameterization of the quercetin-3-Osophoroside. Conditions were set at 1 atm pressure and 310 K. The software generated parameters in the AMBER-compatible format. The flipping of side chains and placement of missing hydrogen atoms at biological pH was done using Protein Prepare application (39) . All mentioned applications are available on PlayMolecule site (www.playmolecule.org). Also, visualization of the structures was done by using CHIMERA tool (www.cgl.ucsf.edu/chimera). In order to study the structural-biological activity, at first the global reactivity descriptors of the quercetin-3-O-sophoroside molecule were calculated and the affinity of the molecule toward the SARS-CoV-2's receptors was evaluated using molecular docking study. The global parameters of the quercetin-3-O-sophoroside molecule were calculated as following: The Ionization potential (I) and electron affinity (A) are given by: Which E HOMO and E LUMO represent the energies of the respective molecular orbitals. The chemical potential μ and the hardness η are expressed in terms of the ionization potential I and the electron affinity A (43): The calculated global reactivity parameters are gathered in Table. 1. Table 1 Global molecular descriptors indicative of the reactive behavior of the quercetin-3-Osophoroside molecule. Calculated result The relatively larger value of the quercetin-3-O-sophoroside molecular hardness with respect to similar value for other antioxidants which were calculated by similar method reveals a remarkable stability of the molecule. In this study, molecular docking simulations between quercetin-3-O-sophoroside and different proteins such as E protein (ion channel) ( (endoribonuclease) (Fig. 2g) , Nsp16 (2'-O-MTase) (Fig. 2h) , Papain-like protease (Fig. 2i) , Papainlike protease (Fig. 2j) , RdRp with RNA (Fig. 2k) , and RdRp without RNA (Fig. 2l) were performed to obtain the respective binding energies, involved amino acid residues, and corresponding linkages between the ligand and the receptors. In this method, the binding energy or docking energy calculated is a set of intracellular energy and ligand internal energy. (Table. 2). Also, as can be seen in Table 2 Fig. 3 for E protein (ion channel) (Fig. 3a) , Helicase NCB site (Fig. 3b) , Main Protease (Fig. 3c ), N protein NCB site (Fig. 3d) , Nsp14 (ExoN) (Fig. 3e) , Nsp14 (N7-MTase) (Fig. 3f) , Nsp15 (endoribonuclease) (Fig. 3g) , Nsp16 (2'-O-MTase) (Fig. 3h) , Papain-like protease (Fig. 3i) , Papainlike protease (Fig. 3j) , RdRp with RNA (Fig. 3k) , and RdRp without RNA (Fig. 3l) . The nearest interacting residues are summarized in Table 3 . (43) . As can be seen in Table1, some of ligand's neighboring sites are located in the catalytic region, which can terminate base pair chain elongation (44) . A number of drugs approved by FDA which contain nucleotide analogues and non-nucleotide compounds have been tested in order to inhibit RdRp (45) (46) (47) (48) . In addition to these compounds, other ones containing phytochemicals and their metabolites have been suggested to inhibit the enzyme (49, 50) . Ala-32, Leu-31, Leu-28, Val-29. These hydrophobic residues cause a reduction in hydrophilic interactions, which is not beneficial to the system. E protein as the smallest corona virus's structural protein, has an essential role in envelope formation, budding, assembly, and modulating viral pathogenesis (51, 52) . Ye et al. (53) showed that the disruption of coronavirus E protein can significantly cripple the virus for this reason. Therefore, it is important to explore some compounds that can inhibit this protein. Several compounds have been proposed to inhibit corona virus's E protein (54, 55) . This protein has a large hydrophobic transmembrane domain, However, modeling this protein without considering the membrane can also provide useful information on how it interacts with compounds that are introduced as drug candidates (55). The prediction of the conformational changes of the protein is the analysis of the structural status of each residue in the protein sequence in three possible forms: helix, sheet, and coil. Structural prediction is based on the fact that the protein structure has a regular arrangement of amino acids that are stabilized by different bonding patterns. The regularity of the structure is the main basis of predictive algorithms. The plot of root mean square deviation (RMSD) was shown in Fig.4 . The RMSD values increased gradually in the first 9 ns, followed by a sharp increase for 4 ns, and after that, the system reached a point of equilibrium. The difference between the maximum and the minimum RMSD values over the rest of the time is about 1nm. It might be attributed to a substantial conformational change of the protein. The second and third peaks in the graph are related to residues (40) (41) (42) (43) (44) (45) and (55) (56) (57) (58) (59) located in loop 4 (L4) and N-terminal of chain A, respectively. In the chain B, residues (102-105) located in loop 3 (L3) have a moderate intensity in the RMSF graph while the most intense peak in the graph is related to residues (110-119) which are the constituent amino acids of α -helix 4 (H4). This instability can be induced by presence of the ligand in the vicinity of these residues. The other peaks in the RMSF graph are related to similar locations in adjacent chains. Fig.7 also shows the structural changes of E protein (Fig. A) after interaction with quercetin-3-Osophoroside complex during 25 ns evolution (Fig. 7B) . Based on this result and already published data (56) (57) (58) (59) , it can be indicated that some potential small molecules can be used in clinical settings to inhibit the main SARS-CoV-2's proteins and enzymes. It should be also noted that cellular and molecular assays (60) along with some classified information for determining protective practices (61) should be considered to further obtain potential details about the control of this disease. In The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Submission of work requires that the piece to be reviewed has not been previously published. Upon acceptance, the Author assigns to the Arabian Journal of Chemistry (ARABJC) the right to publish and distribute the manuscript in part or in its entirety. The Author's name will always be included with the publication of the manuscript. 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