Investigation of interaction between close and open types of SARS-Cov-2 spike glycoprotein with synthesized and natural Compounds as inhibitor; Molecular Docking Study

doi:10.21203/rs.3.rs-38089/v1

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Investigation of interaction between close and open types of SARS-Cov-2 spike glycoprotein with synthesized and natural Compounds as inhibitor; Molecular Docking Study

https://doi.org/10.21203/rs.3.rs-38089/v1

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Purpose Viral diseases are increasingly endangering universal public health because of a shortage of successful antiviral therapies. The novel pandemic 2019 n-Cov2 disease (COVID-19) is recently identified as viral disorder triggered by a new type of coronavirus. This type of coronavirus binds to the host human receptors through the Spike glycoprotein(S) Receptor Binding Domain (RBD). Two types of spike protein have been identified in open and closed states in which the open type causes severe infection. Thus, this receptor is a significant target for antiviral drug design.

Methods Totally 111*2 natural and synthetic compounds were chosen from the PubChem database as ligands. To recognize the ability of direct contact between ligands and the binding site of 2019 n-Cov 2 -ACE2 protein, we have docked all compounds to the protein using AutoDock Vina. The FaF3-Drugs, Pan Assay Intrusion Compounds (PAINS), absorption, distribution, metabolism, excretion (ADME) and Lipinski's rules were used to evaluate the drug-like properties of the identified ligands. Antiviral compound prediction (AVC pred) also was used to assess antivirus properties.

Results The results showed that seven ligands out of all had interactions with spike protein-angiotensin converting enzyme 2 binding site. We have found that six out of seven ligands show drug-like characteristics. We also found that the fluorophenyl and propane groups of ligands had the best interaction with the binding site of the protein.

Conclusion Further, our results showed the ability of these ligands to prevent receptor binding of the spike protein SARS-CoV-2, so they would be considered as novel compounds of COVID-19 therapy drugs.

Bioinformatics

Coronavirus 2019

Spike glycoprotein

Molecular docking

Fluorophenyl

Propane.

Coronaviruses are the large family of viruses that belong to the family of coronaviridae. Based on genomic structures and phylogenetic relationships, the subfamily coronavirinae includes four sorts Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus (Woo et al. 2012). Recently named extreme acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and categorized into the genus Betacoronavirus (Hui et al. 2020), that induce animal and human respiratory and intestinal infections (Vijay, Perlman 2016). Severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome-related coronavirus(MERS-CoV), and Severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) strains share the identity of the genome sequence nearly 79% and 50%, respectively (Lu et al. 2020). However, significant contrasts as far as the study of disease transmission and physiopathology between these three infections have additionally been watched (Cruz et al. 2020; Huang et al. 2020; Wang et al. 2020). 2019-nCoV, classified as SARS-CoV-2, has a higher transmission risk than other in its family. SARS-CoV-2 is quite close to the other two widely studied coronaviruses; MERS-CoV and SARS-CoV (Organization 2020; Tai et al. 2020). However, there are still no antiviral medication and vaccine approved for the treatment and prevention of SARS-CoV-2 infections. Four important structure of coronaviruses are spikes (S), envelopes (E), membranes (M), and nucleocapsid (N) (Zhou et al. 2018; Cui et al. 2019). Angiotensin-converting enzyme 2(ACE2) is a key enzyme that SARS-CoV and several SARS-related coronaviruses connect to it, in order to enter to target cells (Kirchdoerfer et al. 2018; Song et al. 2018). The most current findings suggest that the SARS-CoV-2 attaches to the ACE2 receptor on the host cell surface utilizing the spike protein receptor-binding domain (Goswami, Bagchi 2020; Walls et al. 2020; Li et al. 2005). The glycoprotein transmembrane spike which forms homo-trimer protruding from on the viral surface, helps coronaviruses to entrance into host cells (Walls et al. 2016). The spike glycoprotein on the coronavirus envelope synthesized nearly 1300 amino acids as a single precursor to the polypeptide chain and cleaved by host furin-like proteases into the amino (N)-terminal S1 subunit and the carboxyl (C)-terminal S2 subunit, the host cell connection, receptor binding and the stabilization of host cell membrane and viral membrane fusion during infection are four duties for which glycoprotein spikes are responsible (Du et al. 2009; Millet, Whittaker 2015). In Figures 1A, B, and 1C the homotrimer of SARS-CoV-2 S glycoproteins and a monomer protein respectively are represented. Two types of spike protein have been identified in open and closed states, that the closed SARS-CoV-2 S ectodomain trimer applying 3-fold symmetry with three ACE2-recognition motifs, whose location was meddled focuses on the crystal structure of SARS-CoV S in complex with ACE2(Figure1A) [16]. Opened SARS-CoV-2 S is an asymmetric reconstruction of the trimmer with a single subunit B domain (Figure1B) [15]. On the whole, this information indicates that S glycoprotein trimers present in profoundly pathogenic human coronaviruses seem to be in moderately opened states, although they remain mostly closed in common cold-related human coronaviruses (Guan et al. 2003; Li et al. 2004; Wan et al. 2020). Based on recent evidence the binding affinity of SARS-CoV for hACE2 with the rate of transmissibility, viral replication in distinct organisms, and seriousness of the disease is correlating [29, 30], it is believed that the most pathogenic coronaviruses will indicate S glycoprotein trimers spontaneously make closed and open conformations, as is the case with SARS-CoV-2, SARS-CoV and MERS-CoV, respectively (Walls et al. 2020). S1 and S2 subunits are Two functional subunits responsible for the host cell receptor, viral, and cell membrane combination that forms the spike glycoprotein (Belouzard et al. 2009; Bosch et al. 2003; Walls et al. 2016; Kirchdoerfer et al. 2016). The S1 subunits have two duties: this subunit comprises hl;ost cell attachment domains by identifying molecules of cell surface sugar and attaching to specific cellular receptors (Li 2015, 2016),Therefore, its receptor-binding domain (RBD) is critical in determining cell tropism, host range and zoonotic transmission of coronaviruses(Lu et al. 2015; Graham, Baric 2010). A hydrophobic fusion peptide and two heptad repeat regions compose the S2 subunit (Song et al. 2018). spike receptor-binding domain bound with the cell receptor ACE2 causes the triggers conformational changes in the S1 and S2 subunits, leading to the exposure of the fusion loop and its insertion into target cell membrane(Hofmann, Pöhlmann 2004; Lan et al. 2020). In this study, we have considered 6 different groups of ligands (Table 1): Anti-virus, Flavonoids, Fluorophenyls, Phenylpropanoids, some drugs that have been suggested for SARS-CoV-2, and compounds similar to fluorophenyl groups were virtually screened by Using the PubChem database that 3 compounds finally chosen which were Propane groups. Antiviruses have been used because of their antiviral properties and checking their effectiveness against SARS-CoV-2. Flavonoids are present in nearly all fruits and vegetables, as a category of natural substances with variable phenolic structures (Panche et al. 2016). These natural products are well known for their useful health effects such as antimicrobial activity, antioxidant, anticancer, and antivirus (Cushnie, Lamb 2005; Pietta 2000; Ren et al. 2003; Zhou, Li 2007). The compounds of fluorophenyl are composed of fluoro + phenyl, which are different compounds. As it is shown in the previous study, 2-ﬂuorophenyl, 3-ﬂuorophenyl, and 4-ﬂuorophenyl have antibiotic and antifungal activity so this compounds are used to docking in our study(Saleh et al. 2010). Phenylpropanoids are an enormous class of plant secondary metabolites got from aromatic amino acids phenylalanine in many plants or tyrosine in partial monocots. (Deng, Lu 2017). By having various biological functions, phenylpropanoids are useful for human health, so the systematic research has centered on natural and biotechnologically induced phenylpropanoids for medical usage as antioxidants, anticancer, antiviral, anti-inflammatory, wound healing, and antibacterial substances during the last few decades (Korkina et al. 2011). In this study, set of all six ligand groups will be investigated for interaction with the S1 subunit of SARS-CoV-2 spike glycoprotein by molecular docking. AutoDock vina (http://autodock.scripps.edu) is a popular open-source application for performing molecular docking, the prediction of ligand-receptor interactions. In the drug discovery process, molecular docking is a computationally intensive and prominent method. In this paper, we remember the criticality of research and the development of a COVID-19 drug by attaching ligands to the S glycoprotein RDB, which could assume a compelling role in interfering with the spike refolding procedure and thus repressing viral entry into host cells.

Protein preparation:

As mentioned, the S1 subunit in the B domain is the main cause of the pathogenic difference of the SARS-CoV-2, so throughout this study, only the B chain was examined in both opened and closed types. The structure of the SARS-CoV-2 spike with closed and opened state (respectively with PDB ID: 6vxx and 6vyb) was downloaded from Protein Data Bank (Berman et al. 2000). First, we used modeller 9.2 software for modeling the missing residue that located in subunit S1 for both B chains selected (after modeling the chains to obtain the amino acid number in the 6vxx(closed type) -87 and in the 6vyb (open type) -102 positional difference is the compared to downloaded structures from PDB) (Webb, Sali 2016; Fiser, Do 2000). The B chains and ligands were then translated to pdbqt format to dock in autodock vina software (Trott, Olson 2010). Before docking, polar hydrogens, and gasteiger charges were applied to the configuration of the B chains and ligands. The autodock Vina docking tool was used to test ligand binding on the SARS-CoV-2 B chain. Additionally, blind docking of ligands was done to recognize the possible binding sites in the S1 subunit. For this, the entire protein was covered with the grid box of dimension 36.70 50 70.01Å for opened type protein and 63.29 52.10 50.14 for closed type with grid spacing 1 Å. Finally the conformations with high negative binding energy in binding site that mentioned in the recent study are chosen(Walls et al. 2020; Lan et al. 2020; Yan et al. 2020).

Ligands preparation

ligands' 3-dimensional structure was extracted from the database of ChemSpider and PubChem, and these structures were then translated to PDB format by using the molecular visualization package of Chimera (Meng et al. 2006; Pettersen et al. 2004).

Ligand receptor interaction analysis

The docking results were analyzed using Ligplot+ and Discovery Studio Visualizer tool for a clear view of the best-docked complexes' receptor-ligand interaction (Laskowski, Swindells 2011; BIOVIA 2017; Studio 2008).

Drug-like characteristic

It is important to examine the main parameters associated with absorption, distribution, metabolism, excretion(ADME) properties such as the five rule of Lipinski, drug solubility, pharmacokinetic characteristic, molar refractivity, and drug likeliness in order to produce medicines with a good therapeutic index (Bueno 2020; Lipinski 2004). Development of drugs requires testing ADME progressively earlier in the discovery process, at a period when multiple compounds are regarded but access to physical samples is restricted, so computational prediction of the ADME identified ligands were predicted virtually (Daina et al. 2017). ADME profiling of all the ligands were determined using online software instrument (http://www.swissadme.ch). The original Lipinski RO5 deals with orally active compounds and defines four simple ranges of physicochemical parameters ranging molecular weight (MWT) ≤500, log P ≤5, H-bond donors≤10, H-bond acceptors ≤10) (Lipinski et al. 1997). Moreover, Pan Assay Intrusion Compounds(PAINS) identifies a variety of substructural features that may help recognize compounds that appear as frequent ligands (promiscuous compounds) in several high-throughput biochemical screens (Baell, Holloway 2010), FAF-Drugs3 filtering is used(Lagorce et al. 2015). Infections of SARS-CoV-2 are actively threatening worldwide general health owing to a shortage of successful antiviral therapies, so in our work antiviral compound prediction (AVC pred) for chosen ligands was used (http://crdd.osdd.net/servers/avcpred/batch.php). In the AVCpred method, Experimental percentage inhibitory from ChEMBL, as a large-scale bioactivity database for drug discovery are used to foresees antiviral compounds against HIV, Hepatitis C virus (HCV), Hepatitis B virus (HBV), Human herpesvirus (HHV), and 26 other viruses (Qureshi et al. 2017).

Molecular docking

Identify the ligands that bind to the S_B domain-ACE2 binding site were conducted by molecular docking studies. 111 compounds which downloaded from the ChemSpider and PubChem databases, were subjected to molecular docking approaches. All ligands with their chemical formula, binding affinity in opened type, and S^B domain residues interaction through hydrogen and hydrophobic bonds are shown in Table 1, that the amino acids in the2019 n-Cov 2 -ACE2 binding site are bolded in this table. (all this information for closed type is available as supplementary data file S1). According to molecular docking results, we selected seven identified ligands for drug-like filtering that have hydrogen and hydrophobic interacting in Spike 2019 n-cov2-ACE2 binding site in both closed and opened type that the amino acids in the2019 n-Cov 2 -ACE2 binding site are shown bolede in table 2. Rossicaside A has a hydrophobic binding with Tyr347 in the open state that is part of the binding area with -7.4 Kcal/mol binding energy. 1,2-Ethanediol, 1,2-bis(4-fluorophenyl) with a binding energy of -6.6Kcal/mol in open type forming hydrogen bonds with Gly394 and three hydrophobic bindings that Tyr393 and Tyr403 are in S protein-ACE2 binding site (Figure 2). 1,2-Propanediol, 3,3,3-trifluoro-2-phenyl-, (2R) with binding energy -6.7 Kcal/mol forming a hydrogen bond with Gly394 and its hydrophobic bond were with Tyr393, Asn399, and Tyr403 residues (Figure 3). 1,1-bis(3-fluorophenyl)-2-methoxyethanol with a binding energy of -6.6Kcal/mol in open type forming hydrogen bonds with Gly394, Gln396, Asn399, Gly400 while other hydrophobic interacting residues were Tyr393 Tyr403(Figure 4). 1,1-diphenyl propane-1,2-diol also forming two hydrogen bonds with Gly394 and Asn399 and is also two hydrophobic bonds with Tyr393 and Tyr403(Figure 5). The seventh chosen ligand is (S)-1,1-Diphenylpropane-1,2-diol with -6.2 Kcal/mol binding affinity that form hydrogen bonds with Gly394, Gln396 and Asn399 and hydrophobic bond with Tyr393 and Tyr403(Figure 6). In closed state hydrogen bonds and hydrophobic bond are mentioned in Table1(All hydrogen bonds in closed state showed as supplementary data file S2).

Drug-like characteristic of the chosen ligands

ADME is the guideline that essentially specifies the different molecular characteristic of a compound and is the prime prerequisite to be a possible drug-like (Matter et al. 2001). To assess the pharmacokinetic characteristic of the chosen ligands, we evaluated the Drug Likeliness for 7 chosen ligands based on Lipinski's rule of five (Lipinski et al. 1997). Lipinski 's rule of 5 suggests that weak absorption or permeation is more probable if more than 5 H-bond donors are involved, 10 H-bond acceptors, the molecular weight exceeds 500 Dalton, the calculated high lipophilicity (Log P ) exceeds 5(Lipinski et al. 1997). The qualifying range for molar refractivity was between 40 and 130, with a mean value of 97(Matter et al. 2001). As in Table 3 is shown, just Rossicaside A cannot pass the Lipinski's rule of five, molar refractivity that is more than 130, and it is not a Drug Likeliness with 3 Violations. The remaining 6 chosen ligands passed all the parameters of the MADE (Table3). PAINS filtering to identify the existence of chemical groups belonging to the PAINS category. Six out of seven ligands were accepted as drug-like, and the physicochemical filter passed without any structural caution. The Rossicaside A is discarded which had the catechol group in the PAINS sub-structural moieties. Also, FAF-Drugs3 filtering is rejected for Rossicaside A and other ligands are Accepted by this filtering. In continue we investigated antiviral properties of them. The result of prediction antiviral for chosen compounds are show in table 5 that show respectively Etrinavir, Rossicaside A, 1,1-bis(3-fluorophenyl)-2-methoxyethanol, 1,2-Ethanediol 1,2-bis(4-fluorophenyl), 1,1-diphenylpropane-1,2-diol, (S)-1 1-Diphenylpropane-1 2-diol, 1,2-Propanediol, 3,3,3-trifluoro-2-phenyl-(2R) with general rate 74.78, 47.52, 41.68, 29.87, 28.41, 28.41, 25.53. A bar plot of the percentage of inhibition efficacy in each ligand for HBV, HCV, HHV, HIV, and General (26 viruses) is shown in Figure 7(A, B, C, D, and E). As is clear in figure 7D, final ligands have the most percentage inhibition efficacy on the HIV virus with average efficacy %65/55. The minimum percentage of inhibition efficacy is shown in figure 7C which shows the HHV with average %16/81.

In the specialized field of computer-aided drug designing to discover a new compound, molecular docking is widely used to explore the different forms of the binding interaction between the prospective drug and the various domains or active sites, and binding sites on the target molecules (Raj et al. 2019; Hughes et al. 2011). It's been years that molecular docking is a great tool for the exploration of medicines. This is used to model atomic level binding between proteins and small molecules, which helps us to characterize the actions of small molecules at the target protein binding site (Meng et al. 2011). In viral infections due to the lack of successful antiviral therapies, there is an urgency to speed up the process of drug development to find new and effective drug candidates. Attachment, fusion, and entry into the host cells are 3 duties that glycoprotein of the 2019 novel coronavirus plays important roles in these works that it is a SARS-CoV-2S surface protein(Yan et al. 2020). B chain in this protein is a factor that causes the formation of two open and closed forms of coronavirus that in terms of structural biology is in a heterotrimeric form with three different polypeptide chains: chain A, chain B, and chain C making each monomer (Walls et al. 2020). In this work, the B chain of spike glycoprotein CoV2 in 2 forms closed and opened (PDB ID: 6vyb and 6vxx) were modeled for modeling the missing residue and molecular docking done with about 111 combinations were screened from the ChemSpider and PubChem databases (Table 1) to find the best ligand to block the B-chain binding site connection with ACE2. The compound ID(CID) of selected ligands from PubChem are: CID 13916145, CID 193962, CID 2755890, CID 11095754, CID 53722331, CID 555451, CID 736300, which showed have interaction with Spike 2019 n-cov2-ACE2 binding site residues with the energy of binding affinity, respectively: -7.5 Kcal/mol, -7.4Kcal/mol, -6.7Kcal/mol, -6.7 Kcal/mol, -6.6 Kcal/mol, -6.4 Kcal/mol, -6.2 Kcal/mol. Among all different types of interactions such as H-bond, π-π, amide-π interactions, etc that always analyzed, ligand efficacy refers to the ability to bind the target's binding sites has commonly set out analyzing its hydrogen-bonding pattern and the properties of residues engaged at the binding site (Raj et al. 2019; Hughes et al. 2011). 7 final ligands are: Rossicaside A is a phenylpropanoid, which phenylpropanoids and their derivatives are commonly found in fruits, vegetables, grains of cereals, beverages, spices, and herbs. It is considered that antimicrobial, antioxidant, anti-inflammatory, antidiabetic, anticancer action, and show renoprotective, neuroprotective, cardioprotective, and hepatoprotective effects are multifaceted effects of phenylpropanoids (Jia et al. 2018; Shyr et al. 2006). Rossicaside A is an antioxidant that is used in this sudy (Gálvez et al. 2006). Etravirine is a reverse transcriptase inhibitor of the next-generation, non-nucleoside, that administered orally and it is endorsed for the treatment of Infection of HIV-1 in experienced grown-up patients who have proof viral replication and are harboring HIV-1 strains resistant to other antiretrovirals (ARV) agents (Croxtall 2012). There are different combinations of this structure, 1,2-Ethanediol, 1,2-bis(4-fluorophenyl) and 1,1-bis(3-fluorophenyl)-2-methoxyethanol are 2 fluorophenyl compounds that in our study formed hydrogen and hydrophobic interactions in S protein-ACE2 binding area so we also use three ligands (1,2-Propanediol, 3,3,3-trifluoro-2-phenyl-, (2R), 1,1-diphenyl propane-1,2-diol and (S)-1,1-Diphenylpropane-1,2-diol) that had closed structure to fluorophenyl compounds. As in drug-like characteristics of the chosen ligands analysis shown, we conclude that most of the important pharmacophoric characteristics required for an adequate restraint of the S_B protein are accepted by six ligands recognized from the PubChem database. Moreover, their binding with chain B in both type forms a stable complex with a sturdy network of hydrogen, hydrophobic bonds and important residues, namely: Tyr347,as Phe377, Tyr393,Gly394, Gln396, Asn399, Gly400, Tyr403, Tyr408, Gly409, Gln411, Asn414 that were recently predicted as close contact residues with the human cell host receptor (Shang et al. 2020; Walls et al. 2020). Using the ADMEtox filtering, all ligands identified were assessed for pharmacokinetic properties. The rule of five Lipinski theory is commonly used to determine possible reactions between medication and other non-drug target molecules. In Lipinski’s rule, it is mentioned that for any compound to be chosen as a potential drug it ought to have (a) Molecular mass < 500 Dalton (b) high lipophilicity (expressed as LogP<5) (c) less than 5 hydrogen bond donors (d) Less than 10 hydrogen bond acceptors (e), also molar refractivity between 40-130 and drug Likeliness are 2 another factor that investigated in ADMEtox filtering. In the event that a compound has more than two of the previously mentioned measures, then the compound is probably going to be a potential drug candidate (Table 3). Also PAINS and FAF-Drugs 3 filtering are 2 other drugs-filtering that FAF-Drugs 3 is a program for filtering large compound libraries in silico screening experiments or related modeling studies and PAINS filtering can process hundreds and thousands of compounds in seconds and are in widespread current use to identify PAINS in order to exclude them from further analysis. In table 4 it is shown that in 7 final ligands just Rossicaside A is rejected also by these filtering and others are accepted. Antiviral compound prediction is the final analysis that in this study investigated for chosen ligands, which AVCpred is an instrument to accelerate the drug discovery procedure to recognize novel and efficacious antivirus drug candidates (Table 5, Figure 7). The ligands chosen have the most percent inhibition of HIV efficacy as shown in Figure 7D, and in the other groups of viruses, they have the antiviral properties that show that final ligands can be used as antivirus drugs. Thus we suggest that all of these ligands except Rossicaside A have the potential ability to be an effective drug. In this work we used molecular docking to reveal whether there was any close interaction with 2019 n-cov2 ligands and S_B proteins, the result showed acceptable binding of Etravirine, 1,2-Ethanediol, 1,2-bis(4-fluorophenyl), 1,2-Propanediol, 3,3,3-trifluoro-2-phenyl-(2R), 1,1-bis(3-fluorophenyl)-2-methoxy ethanol, 1,1-diphenyl propane-1,2-diol and (S)-1,1-Diphenylpropane-1,2-diol of calcitriol with some amino acids of the binding site of B chain of spike protein through hydrogen and hydrophobic interactions bonds. It is noteworthy that in this study we decided to share our discoveries with all the researchers who work for experimental drug verification in the area of anti-SARS-CoV-2 research over the world.

The main objective of the present study was to find the best ligand by molecular docking and evaluation of binding interaction against the B chain SARS-CoV-2 with ACE2. Seven compounds from the PubChem database were chosen based on interaction against the binding site of the B chain SARS-CoV-2-ACE2. Six final ligands were selected according to drug-like characteristic (CID 193962, CID 2755890, CID 11095754, CID 53722331, CID 555451, CID 736300). These results show that these compounds could potentially be used as a drug against SARS-CoV-2.

Acknowledgments The authors are thankful for helpful feedback and observations to the reviewers and editors, which helped enhance the paper quality. The authors do not have any relevant affiliations or financial involvement with any organization or entity having a financial interest.

Compliance with ethical standards

Conflict of interest The authors declare that there are no conflicts of interest.

Ethical approval This article does not contain any studies with human participants and animals performed by any of the authors.

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Table 1 Result of 6vyb molecular docking with all ligands, which are under study in this work. 5 ligand groups are ranked by binding affinity.

Ligand name

Chemical formula

Binding Affinity

(Kcal/mol)

Residues interaction with Ligand through hydrogen binding

Residues interaction with Ligand through Hydrophobic binding

Anti-viruses

Indinavir

C₃₆H₄₇N₅O₄

-8.1

Asn241, Asn335

Phe240, Phe272, Leu339

Maraviroc

C₂₉H₄₁F₂N₅O

-8

G424

Phe227, Ile230, Thr231, Asp287, Lys426

Raltegravir

C₂₀H₂₁FN₆O₅

-8

Ser269, Trp334, Arg407

Val265

Saquinavir

C₃₈H₅₀N₆O₅

-7.7

Ser264, Pro425

Val225, Ile230, Lys427

Methylprednisolone

C₂₂H₃₀O₅

-7.6

Arg253, Thr328, Gln414

Phe362

Etravirine

C₂₀H₁₅BrN₆O

-7.5

Ser271

Phe240, Asn241, Phe272, Trp334, Leu339

Acteoside

C₂₉H₃₆O₁

-7.3

Phe240, Asn241, Asn335, Asn338, Gln404

Phe272, Trp334

Cyclosporin A

C₆₂H₁₁₁N₁₁O₁₂

-7.2

Arg253

Phe290, Tyr294, Phe327, Thr328, Phe362, Leu415, Leu416

Nelfinavir

C₃₂H₄₅N₃O₄S

-7.1

Thr421, Cys423

Phe227, Pro228, Ile230, Thr231, Val260, Lys426

Efavirenz

C₁₄H₉ClF₃NO₂

-7

Thr328

Tyr294, Pro324, Phe362

Aldosterone

C₂₁H₂₈O₅

-6.9

Arg253, Thr328, Glu414

Phe362

Delavirdine

C₂₂H₂₈N₆O₃S

-6.9

Asn258

Phe227, Asn258

Alclometasone

C₂₂H₂₉ClO₅

-6.8

Thr328, Pro361, Phe362

Phe362, Glu414

Abacavir

C₁₄H₁₈N₆O

-6.7

Ser269. Ser271

Val265, Leu266, Phe272

Atazanavir

C₃₈H₅₂N₆O₇

-6.6

Arg253

Phe290, Tyr294, Phe328, Phe362, Leu415, Leu416

Imiquimod

C₁₄H₁₆N₄

-6.6

Leu266, Phe272, Trp334

Lopinavir

C₃₇H₄₈N₄O₅

-6.6

Cys259

Phe227, Pro228, Ile230, Thr231, Asn258, Val260, Lys426

Entecavir

C₁₂H₁₅N₅O₃

-6.5

Cys259

Sofosbuvir

C₂₂H₂₉FN₃O₉P

-6.5

Cys259, Asn442

Phe227, Pro228, Ile230, Asn258, Thr421, Lys426

Zidovudine

C₁₀H₁₃N₅O₄

-6.4

Ala420, Gly424

Stavudine

C₁₀H₁₂N₂O₄

-6.3

Ser269, Ser271

Phe240, Phe272, Phe272, Leu339

Telbivudine

C₁₀H₁₄N₂O₅

-6.3

Ser271, Arg407

Phe240, Phe272, Trp334, Leu339

Zalcitabine

C₉H₁₃N₃O₃

-6.3

Ser271

Phe240, Leu266, Trp334

Didanosine

C₁₀H₁₂N₄O₃

-6.1

Phe240, Asn241, Ser269, Ser271

Phe272

Nevirapine

C₁₅H₁₄N₄O

-6.1

Phe240, Phe272, Trp334

Ribavirin

C₈H₁₂N₄O₅

-6.1

Arg352, Arg355, Ser367, Gln369

Telaprevir

C₃₆H₅₃N₇O₆

-6.1

Phe227, Pro228, Ile230, Val260, Lys426, Asn442

Emtricitabine

C₈H₁₀FN₃O₃S

-6

Cys259, Thr421, Gly424, Lys426

Ganciclovir

C₉H₁₃N₅O₄

-5.9

Phe240, Trp334, Arg407

Ala242, Ser269, Ser271, Arg407

Fosamprenavir

C₂₅H₃₆N₃O₉PS

-5.8

Thr231

Phe227, Pro228, Val260,Lys426

Penciclovir

C₁₀H₁₅N₅O₃

-5.8

Phe227, Pro228, Asp262, Lys426

Ile230, Pro425, Lys427

Rimantadine

C₁₂H₂₁N

-5.8

Cys234, Gly237

Leu233, Phe236, Val265, Leu266

Lamivudine

C₈H₁₁N₃O₃S

-5.7

Pro228, Cys259, Thr421, Gly424, Lys426

Thr231

Valganciclovir

C₁₄H₂₂N₆O₅

-5.7

Phe240, Ser269, Ser271

Aciclovir

C₈H₁₁N₅O₃

-5.6

Phe240, Asn241, Ser269, Ser271

Gancyclovir

C₉H₁₃N₅O₄

-5.6

Phe240, Asn241

Ritonavir

C₃₇H₄₈N₆O₅S₂

-5.6

Pro228, Thr231, Val260, Asn442

Tenofovir

C₉H₁₄N₅O₄P

-5.6

Trp334

Phe272, Trp334

Valaciclovir

C₁₃H₂₀N₆O₄

-5.6

Asn241, Ser269, Trp334

Leu339

Famciclovir

C₁₄H₁₉N₅O₄

-5.5

Ala420

Phe227, Ile230, Thr231, Val260

Idoxuridine

C₉H₁₁IN₂O₅

-5.5

Trp334

Oseltamivir

C₁₆H₂₈N₂O₄

-5.5

Asp318, Thr328, Ser412

Pro324, Thr328, Phe362, Glu414

Zanamivir

C₁₂H₂₀N₄O₇

-5.5

Arg226, Ser428, Gln478

Amantadine

C₁₀H₁₇N

-5.3

Pro228, Asn229

Val260, Lys426

Docosanol

C₂₂H₄₆O

-3.8

Ile230, Leu233, Phe236, Val265, Leu266, Pro425

Methoxyethanol

C₃H₈O₂

2.9

Arg352, Lys356, Ser367, Glu369

Enfuvirtide

C₂₀₄H₃₀₁N₅₁O₆₄

-2.2

Ser257

Drug of cov2

Baloxavir marboxil

C₂₇H₂₃F₂N₃O₇S

-7.7

Phe227, Pro228, Ile230, Thr231, Lys426, Asn442

Indomethacin

C₁₉H₁₆ClNO₄

-7

Pro228

Ile230, Thr231, Val260, Lys426

Azvudine

C₉H₁₁FN₆O₄

-6.2

Cys423, Gly424, Lys426

Oseltamivir

C₁₆H₂₈N₂O

-5.4

Thr328, Ser412

Pro324, Thr328, Pro361, Phe362, Glu414

Chloroquine

C₁₈H₂₆ClN₃

-5.3

THR328

Tyr294, Thr328, Pro361, Phe326, Glu414

Favipiravir

C₅H₄FN₃O₂

-5

Val239, Ala246, Asn252, Ser297

Flavonoids

Ononin

C₂₂H₂₂O₉

-7.8

Thr283, Asp287, Lys427

Ile230, Pro425

Genistein

C₁₅H₁₀O₅

-7.3

Asn338

Phe272, Leu339

Luteolin

C₁₅H₁₀O₆

-7.2

Ser273, Thr274, Tyr278, Tyr406

Lys276, Val305, Arg306

Morin

C₁₅H₁₀O₇

-7.2

Asn241, Asn338

Phe240

Fisetin

C₁₅H₁₀O₆

-7.1

Asp326, Thr328, Pro361, Phe413

Pro324, Pro361

Taxifolin

C₁₅H₁₂O₇

-7.1

Ala242, Trp334, Arg407

Phe240, Asn241, Phe272, Trp334, Leu339

Galangin

C₁₅H₁₀O₅

-7

Asn241, Asn338

Phe240

Isorhamnetin

C₁₆H₁₂O₇

-6.9

Ser269, Asn338

Phe240, Phe272

Naringenin

C₁₅H₁₂O₅

-6.8

Ala242, Trp334, Arg407

Phe240, Asn241, Phe272, Trp334, Leu339

Quercetin

C₁₅H₁₀O₇

-6.6

Asp326, Thr328, Phe413

Pro361, Phe362

Fluorophenyl

1,2-Ethanediol, 1,2-bis(4-fluorophenyl)

C₁₄H₁₂F₂O₂

-6.7

Gly394

Asn319, Tyr393

Tyr403

1,1-bis(3-fluorophenyl)-2-methoxyethanol

C15H14F2O2

-6.6

Gly394, Gln396

Asn399, Gly400

Tyr393, Tyr403

Phenylpropanoid

Telmisartan

C₃₃H₃₀N₄O₂

-8.8

Asp262

Val260, Ala261, Gly424,Pro425, Lys426,Lys427

Sennoside

C₄₂H₃₈O₂₀

-8.6

Arg253, Asp326, Thr328, Ser412, Arg364

Phe327, Lys360, Pro361,Phe362,Phe413, Glu414

Glycyrrhizic acid

C₄₂H₆₂O₁₆

-8.3

Pro228, Cys259, Cys423,

Thr421, Lys426

Phe227, Asn229, Ile230,Arg287, Leu288, Cys289, Ala420, Val422

Verbascoside

C₂₉H₃₆O₁₅

-8.1

Val239, Ser247, Asn252, Ala250, Ser297, Asn348

Arg244, Phe245, Ala246, Trp251, Tyr349, Leu350

Orobanchoside

C₂₉H₃₆O₁₆

-8

Cys259, Ala420, Thr421, Cys423,

Trp334, Asn335, Ser336, Asn337, Asn338, Ala270, Ser271, Phe274, Ser273

Arenarioside

C₃₄H₄₄O₁₉

-7.9

Pro228, Asn229, Thr421, Lys426, Asn442, Cyx259, Gln462

Phe227, Ile230, Asn258, Cys259, Val260, Val422, Cys423, G424, Pro425

Isomartynoside

C₃₁H₄₀O₁₅

-7.8

Ser264, Pro425

Gly424, Lys426, Lys427, Ser428, Val260, Ala261, Asp262

Poliumoside

C₃₅H₄₆O₁₉

-7.8

Thr421, Pro228, Cys259

Phe227, Asn229, Ile230, Asn258, Val260, Asp287, Leu288, Cys289, Val422, Cys423, Gly424

Teucrioside

C₃₄H₄₄O₁₉

-7.7

Asp262, Ser264, Pro425, Ser428, Gln478

Phe227, Pro228, Asn229, Ile230, Gly424, Lys426, Lys427

Angoroside A

C₃₄H₄₄O₁₉

-7.7

Cyx259, Gln462, Pro477

Asn258, Val260

Pheliposide

C₃₆H₄₆O₂₀

-7.6

Asn232, Leu233, Gly237, Asn241, Thr243, Asp262

Cys234, Pro235, Phe236, Ala 242, Val260, Ala261

Rutin

C₂₇H₃₀O₁₆

-7.5

Arg253, Asp326, Thr328, Pro361, Arg364, Phe413, Gln414

Phe327, Gly329, Ser412

Forsythoside B

C₃₄H₄₄O₁₉

-7.5

Pro228, Cys259, Lue288, Ala420, Cys423, Gly424, Lys426

Pro228

Rossicaside A

C₃₅H₄₆O₂₀

-7.4

Gln238, Val239, Ser247, Thr249, Trp251, Asn252, Arg253, Ser297

Lys249, Ala250, Tyr347, Asn348, Tyr349, Leu350

Forsythiaside A

C₂₉H₃₆O₁₅

-7.4

Phe240, Asn241, Ala270, Ser271, Phe272, Asn335, Asn338, Tyr406

Ser273, Trp334, Ser336, Asn337, Val401

Purpureaside C

C₃₅H₄₆O₂₀

-7.4

Leu288, Ala420, Thr421, Gln462

Phe227

Hesperidin

C₂₈H₃₄O₁₅

-7.4

Pro228, Cys259, Thr421, Lys426

Phe227, Val260

Isoverbascoside

C₂₉H₃₆O₁

-7.4

Ala244, Ser247, Trp251, Asn252, Ser297, Asn348

Ala246, Phe245, Tyr249, Ala250

Leucosceptoside A

C₃₀H₃₈O₁₅

-7.4

Asp326, Thr328, Pro361, Glu414, Leu415

Tyr294, Pro 324, Phe362, Leu415

corosolic acid

C₃₀H₄₈O₄

-7.3

Ser273, Thr406

Val305, Arg306, Ala309, Val401, Tyr406

Calceolarioside C

C₂₈H₃₄O₁₅

-7.2

Asn241, Ser271, Ser296, Trp334, Asn335, Asn338

Asn241

Eukovoside

C₃₀H₃₈O₁₅

-7.2

Val239, Phe245, Ser247, Asn348, Ser297

Tyr249, Ile366, Thr368

Angoroside C

C₃₆H₄₈O₁₉

-7.1

Asn229, Pro228, Thr231, Cys259, Thr421, Cys423, Lys426

Phe227, Pro228, Val260

Conandroside

C₂₈H₃₄O₁₅

-7.1

Gln238, Ala250, Trp251, Asn252, Ser247, Ser297, Asn348

Ala250, Ile366

Losartan

C₂₂H₂₃ClN₆O

-7.1

Ser273, Arg306

Thr274, Lys276, Val305, Arg306, Val331, Val401

Martynoside

C₃₁H₄₀O₁₅

-7.1

Ala246, Ser247, Asn252, Ser297, Asn348

Tyr249, Ile366

Suspensaside

C₂₉H₃₆O₁₆

-7.1

Arg253, Thr328, Lys360, Arg364, Phe413, Glu414

Tyr294, Phe362

Cistanoside D

C₃₁H₄₀O₁₅

-7

Thr328, Phe413, Gly414, Leu415

Tyr294, Pro324, Pro361, Phe362,Leu415

Osmanthuside B

C₂₉H₃₆O₁₃

-7

Cys259, Ala420, Thr421, Cys423

Phe227, Pro228, Thr231, Val260, Lys426, Pro477

Tubuloside A

C₃₇H₄₈O₂₁

-6.9

Arg253, Thr328, Asp326, Phe362, Arg364

Pro324, Phe362, Glu363, Glu414

Grayanoside B

C₂₆H₄₂O₉

-6.9

Cys259, Thr421, Asn442

Phe227, Thr231, Lys426

Campneoside

C₃₀H₃₈O₁₆

-6.7

Pro228, Asn229, Cys259, Val260, Cys423

Gly424

Val260

Cistanoside C

C₃₀H₃₈O₁₅

-6.7

Pro228, Asn229, Cys259, Cys423

Phe227, Val260

Grayanoside A

C₂₄H₂₈O₁₀

-6.7

T328, Pro361, Phe413

Tyr294, Pro324, Phe362

Oleuropein

C₂₅H₃₂O₁₃

-6.5

Thr231, Asn258, Leu288, Ala420, Gly424

THE231

Stachyoside

C₂₅H₂₈N₂O₈

-6.3

Arg253, Asp261, Pro361

Tyr294, Phe362

Tubuloside C

C₃₇H₄₈O₂₁

-6.3

Arg253, Thr325, Arg364

Pro324, Pro361, Phe362, Glu414, Leu416

Salidroside

C₁₄H₂₀O₇

-6.1

Ala242, Ser269, Thr334, Arg407

Phe240, Trp334

Propane

1,2-Propanediol, 3,3,3-trifluoro-2-phenyl-, (2R)

C9H9F3O2

-6.7

Gly394

Tyr393, Asn399

Tyr403

1,1-diphenyl propane-1,2-diol

C₁₄H₁₄O₂

-6.4

Gly394, Asn399

Arg301, Tyr393

TYR403

(S)-1,1-Diphenylpropane-1,2-diol

C15H16O2

-6.2

Gly394, Gln396

Asn399

Tyr393, Tyr403

Table 2 Summary of top seven ranked ligands screened against RBD of Spike 2019 n-cov2, with their respective classification, Chemical formula, binding affinity, hydrogen, and hydrophobic interacting residues.

Ligand name	Pubchem ID	Open state			Closed state
Ligand name	Pubchem ID	Binding Affinity (Kcal/mol)	Hydrogen bond	Hydrophobic bond	Binding Affinity (Kcal/mol)	Hydrogen bond	Hydrophobic bond
Rossicaside A	13916145	-7.5	Gln238 Val239 Ser247 Thr249 Trp251 Asn252 Arg253 Ser297	Lys249 Ala250 Tyr347Asn348 Tyr349 Leu350	-6.8	Ala257 Ser284 Ser286 Asn353 Asn350	Phe255 Leu354
Etravirine	193962	-7.4	Ser271	Phe240 Asn241 Trp334 Leu339	-6.7	Gly409	Phe377 Glu429
1,2-Ethanediol, 1,2-bis(4-fluorophenyl)	2755890	-6.7	Gly394	Asn319 Tyr393 Tyr403	-6.7	-	Tyr408 Asn414 Tyr418
1,2-Propanediol, 3,3,3-trifluoro-2-phenyl-(2R)	11095754	-6.7	Gly394	Tyr393 Asn399 Tyr403	-6.7	Asn414	Tyr408 Asn414
1,1-bis(3-fluorophenyl)-2-methoxyethanol	53722331	-6.6	Gly394 Gln396 Asn399 Gly400	Tyr393 Tyr403	-6.6	Gly409 Gln411 Asn414 Gly415	Tyr408 Asn414Tyr418
1,1-diphenyl propane-1,2-diol	555451	-6.4	Gly394 Asn399	Arg301 Tyr393 TYR403	-6.4	Gln411 Asn414	Arg316 Tyr408 Tyr418
(S)-1,1-Diphenylpropane-1,2-diol	736300	-6.2	Gly394 Gln396 Asn399	Tyr393 Tyr403	-6.4	Gly409 Asn414	Arg316 Tyr408 Tyr418

Table 3 ADME Properties of selected ligands against S^B domain.

Ligands

ADME Properties

Drug

Likeliness

1,1-diphenyl propane-1,2-diol

Molecular weight (<500 Da)

228.29 g/mol

Yes

LogP (<5)

2.85

H-bond donar (5)

H-bond acceptor (<10)

Molar Refractivity (40-130)

67.72

Violations

1,2-Propanediol, 3,3,3-trifluoro-2-phenyl-(2R)

Molecular weight (<500 Da)

206.16 g/mol

Yes

LogP (<5)

1.59

H-bond donar (5)

H-bond acceptor (<10)

Molar Refractivity (40-130)

43.42

Violations

1,1-bis(3-fluorophenyl)-2-methoxyethanol

Molecular weight (<500 Da)

264.27 g/mol

Yes

LogP (<5)

2.84

H-bond donar (5)

H-bond acceptor (<10)

Molar Refractivity (40-130)

67.55

Violations

1,2-Ethanediol, 1,2-bis(4-fluorophenyl)

Molecular weight (<500 Da)

250.24 g/mol

LogP (<5)

1.76

H-bond donar (5)

H-bond acceptor (<10)

Molar Refractivity (40-130)

62.94

Violations

Etravirine

Molecular weight (<500 Da)

435.28 g/mol

Yes

LogP (<5)

3.2

H-bond donar (5)

H-bond acceptor (<10)

Molar Refractivity (40-130)

109.56

Violations

Rossicaside A

Molecular weight (<500 Da)

786.73 g/mol

LogP (<5)

2.79

H-bond donar (5)

H-bond acceptor (<10)

Molar Refractivity (40-130)

180.81

Violations

(S)-1,1-Diphenylpropane-1,2-diol

Molecular weight (<500 Da)

228.29 g/mol

Yes

LogP (<5)

2.15

H-bond donar (5)

H-bond acceptor (<10)

Molar Refractivity (40-130)

67.72

Violations

Table 4 FAF-Drugs3 and pan assay interference (PAINS) filtering of 7 identified ligands.

N	Ligand	FAF-Drugs3 filtering	PAINS filtering
1	1,1-diphenylpropane-1,2-diol	Accepted	None
2	1,2-Propanediol, 3,3,3-trifluoro-2-phenyl-(2R)	Accepted	None
3	1,1-bis(3-fluorophenyl)-2-methoxyethanol	Accepted	None
4	1,2-Ethanediol, 1,2-bis(4-fluorophenyl)	Accepted	None
5	Etrinavir	Accepted	None
6	Rossicaside A	Rejected	catechol
7	(S)-1,1-Diphenylpropane-1,2-diol	Accepted	None

Table 5 AVCpred analysis for seven final ligands.

N	Ligand	General	HBV	HCV	HHV	HIV
1	1,1-diphenylpropane-1,2-diol	28.41	26.79	24.95	16.43	75.45
2	1,2-Propanediol, 3,3,3-trifluoro-2-phenyl-(2R)	25.53	22.97	27.15	18.31	59.56
3	1,1-bis(3-fluorophenyl)-2-methoxyethanol	41.68	26.57	31.10	10.74	63.49
4	1,2-Ethanediol, 1,2-bis(4-fluorophenyl)	29.87	26.41	39.13	7.45	61.41
5	Etrinavir	74.78	22.53	38.38	25.04	70.97
6	Rossicaside A	47.52	21.03	42.72	23.27	52.53
7	(S)-1,1-Diphenylpropane-1,2-diol	28.41	26.79	24.95	16.43	75.45

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Investigation of interaction between close and open types of SARS-Cov-2 spike glycoprotein with synthesized and natural Compounds as inhibitor; Molecular Docking Study

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Abstract

Figures

Introduction

Methods

Protein preparation:

Ligands preparation

Ligand receptor interaction analysis

Drug-like characteristic

Results

Molecular docking

Drug-like characteristic of the chosen ligands

Discussion

Conclusion

Declarations

References

Tables

Supplementary Files

Status:

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