Structural implications of SARS-CoV-2 Surface Glycoprotein N501Y mutation within receptor-binding domain [499-505]–computational analysis of the most frequent Asn501 polar uncharged amino acid mutations

The aim of this study was to evaluate the impact of the most frequent Asn501 polar uncharged amino acid mutations upon important structural properties of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Surface Glycoprotein RBD–hACE2 (human angiotensin-converting enzyme 2) heterodimer. Mutations N501Y, N501T and N501S were considered and their impact upon complex solubility, secondary motifs formation and intermolecular hydrogen bonding interface was analyzed. Results and findings are reported based on 50 ns run in Gromacs molecular dynamics simulation software. Special attention is paid on the biomechanical shifts in the receptor-binding domain (RBD) [499-505]: ProThrAsn(Tyr)GlyValGlyTyr, having substituted Asparagine to Tyrosine at position 501. The main findings indicate that the N501S mutation increases SARS-CoV-2 S-protein RBD–hACE2 solubility over N501T, N501 (wild type): (Formula presented.), (Formula presented.). The N501Y mutation shifts (Formula presented.) -helix S-protein RBD [366-370]: SerValLeuTyrAsn into π-helix for t > 38.5 ns. An S-protein RBD [503-505]: ValGlyTyr shift from (Formula presented.) -helix into a turn is observed due to the N501Y mutation in t > 33 ns. An empirical proof for the presence of a Y501-binding pocket, based on RBD [499-505]: PTYGVGY (Formula presented.) 's RMSF peak formation is presented. There is enhanced electrostatic interaction between Tyr505 (RBD) phenolic -OH group and Glu37 (hACE2) side chain oxygen atoms due to the N501Y mutation. The N501Y mutation shifts the (Formula presented.) hydrogen bond into permanent polar contact;(Formula presented.);(Formula presented.). © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Hydrogen Bonding (Base Pairing) in Antiviral Activity.

Base pairing based on hydrogen bonding has, since its inception, been crucial in the antiviral activity of arabinosyladenine, 2'-deoxyuridines (i.e., IDU, TFT, BVDU), acyclic nucleoside analogues (i.e., acyclovir) and nucleoside reverse transcriptase inhibitors (NRTIs). Base pairing based on hydrogen bonding also plays a key role in the mechanism of action of various acyclic nucleoside phosphonates (ANPs) such as adefovir, tenofovir, cidofovir and O-DAPYs, thus explaining their activity against a wide array of DNA viruses (human hepatitis B virus (HBV), human immunodeficiency (HIV) and human herpes viruses (i.e., human cytomegalovirus)). Hydrogen bonding (base pairing) also seems to be involved in the inhibitory activity of Cf1743 (and its prodrug FV-100) against varicella-zoster virus (VZV) and in the activity of sofosbuvir against hepatitis C virus and that of remdesivir against SARS-CoV-2 (COVID-19). Hydrogen bonding (base pairing) may also explain the broad-spectrum antiviral effects of ribavirin and favipiravir. This may lead to lethal mutagenesis (error catastrophe), as has been demonstrated with molnutegravir in its activity against SARS-CoV-2.

Antiviral activitiy of curcumin, demethoxycurcumin, bisdemethoxycurcumin and cyclocurcumin compounds of Curcuma longa against NSP3 on SARS-CoV-2

SARS-CoV-2 genome encodes two large polyproteins (pp), pp1a and pp1ab which are cleaved and transformed into a mature form by a protease, non-structural protein 3 (NSP3). NSP3 is encoded by open reading frame (ORF) 1a/b. Curcuma longa (C. longa) or turmeric has been documented to have antiviral effects. The aim of this study was to assess the viral activities of C. longa against SARS-CoV-2 focusing on its potency to inhibit viral replication by targeting NSP3. PubChem databases were used to obtain the metabolic profile of C. longa. The compound's interaction with nucleocapsid was analyzed using molecular docking with Molegro Virtual Docker. Bioinformatics analysis based on rerank score presents all compounds of C. longa have higher binding affinity than the native ligand with cyclocurcumin as the lowest score (-128.38 kcal/mol). This anti-viral activity was hypothesized from the similarity of hydrogen bonds with amino acid residues Ser 128 and Asn 40 as key residues present in Ribavirin. This study reveals that C. longa is the potential to be developed as an antiviral agent through replication inhibition in SARS-CoV-2 targeting its replication mediated by NSP3.

Crystal Growth, Structural, Vibrational, Effects of Hydrogen Bonding(C-H…O and C-H…N), Chemical Reactivity, Antimicrobial Activity, Inhibitory Effects and Molecular Dynamic Simulation of 4-Methoxy-N-(Nitrobenzylidene)-Aniline

The present study aims to provide deeper knowledge about the structural, vibrational, chemical, antimicrobial activity, molecular dynamic simulation and drug likeness of synthesized compound 4-Methoxy-N-(nitrobenzylidene)-aniline. The FT-IR and FT-Raman spectra of 4-Methoxy-N-(nitrobenzylidene)-aniline have been recorded in the powder form in the region 4000–500 cm−1 and 3500–50 cm−1. The vibrational analysis were carried out with the help of normal coordinate analysis (NCA). The molecular geometry, hydrogen bonding interaction and vibrational frequencies have been calculated using the density functional method (DFT/B3LYP) with 6-311 G (D) basis set. The natural bond orbital (NBO), atoms in molecule (AIM), and Hirshfeld surface analysis and RDG were applied to evaluate the relative strength of hydrogen bond interactions and represent their effect on the stabilities of molecular arrangements. Related molecules were compared by computation in order to understand the effect of non-bonded interactions (i.e. intermolecular and intramolecular hydrogen bonding). The HOMO and LUMO analysis was used to determine the charge transfer within the molecule. Furthermore, the in vitro antimicrobial study was carried out for the title compound against Aspergillus niger and Staphylococcus aureus. The antimicrobial activity was confirmed on the compounds with molecular docking (A.niger, S.aureus, Homosapians, Sars-Cov-19 and anticancer) studies and molecular dynamic simulation. The non-linear optical (NLO) properties were also analyzed for the molecules.

Efficacy evaluation of quercetin and its analogues on the main protease enzyme of the COVID-19 using molecular docking studies

Introduction: COVID-19 is an acute respiratory infectious disease caused by the SARS-CoV-2 virus. There is an urgent need to discover antiviral drugs for better performance against new strains of coronaviruses (CoVs) due to the rapid spread of the disease despite scientific advances in vaccine development. This study aimed to evaluate the efficacy of quercetin and its analogues on the COVID-19 Mpro enzyme. Material & Methods: In this descriptive-analytical study, the three-dimensional structures of quercetin analogues (20 compounds), standard drugs (ritonavir and lopinavir), and the COVID-19 Mpro enzyme were obtained from PubChem and PDB databases for bioinformatics study, respectively. Molecular docking studies of the compounds on theMpro were performed using MOE-2014 software. Afterward, the physicochemical properties and biological activity of the compounds were predicted using Swiss ADME, PASS, and Swiss Target Prediction software. Findings: The findings of the present study showed that the most important bonds involved in drug-receptor binding are hydrogen, hydrophobic, and - interaction bonds. The best docking results were obtained for Baicalein, Genistein, Naringenin, and Quercetin compounds with strong binding energy (-12.83 to -13.54 kcal/mol), compared to ritonavir and lopinavir. These compounds have a greater tendency to bind to the catalytic amino acids His41 and Cys145 and other key amino acids of the active site of the COVID-19 Mpro enzyme. Discussion & Conclusion: Based on the results of bioinformatics studies, quercetin analogues had more effective inhibition than standard chemical drugs due to their suitable placement in the active site of the main protease enzyme of COVID-19 and can be good candidates for in vitro and in vivo studies.

Molecular docking analysis of novel quercetin derivatives for combating SARS-CoV-2

Quercetin belongs to the flavonoid family, which is one of the most frequent types of plant phenolics. This flavonoid compound is a natural substance having a number of pharmacological effects, including anticancer and antioxidant capabilities, as well as being a strong inhibitor of various toxicologically important enzymes. We discuss the potential of newly recently synthesized quercetin-based derivatives to inhibit SARS-CoV-2 protein. ADMET analysis indicated that all of the studied compounds had low toxicities and good absorption and solubility properties. The molecular docking results revealed that the propensity for binding to SARS-CoV-2 main protease is extraordinary. The results are remarkable not only for the binding energy values, which outperform several compounds in prior studies, but also for the number of hydrogen bonds formed. Compound 7a was capable of forming 10 strong hydrogen bonds as well as interact to the protein receptor with a binding energy of -7.79 kcal/mol. Therefore, these compounds should be highlighted in further experimental studies in the context of treating SARS-CoV-2 infection and its effects.

Towards Quantum-Chemical Level Calculations of SARS-CoV-2 Spike Protein Variants of Concern by First Principles Density Functional Theory.

The spike protein (S-protein) is a crucial part of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with its many domains responsible for binding, fusion, and host cell entry. In this review we use the density functional theory (DFT) calculations to analyze the atomic-scale interactions and investigate the consequences of mutations in S-protein domains. We specifically describe the key amino acids and functions of each domain, which are essential for structural stability as well as recognition and fusion processes with the host cell; in addition, we speculate on how mutations affect these properties. Such unprecedented large-scale ab initio calculations, with up to 5000 atoms in the system, are based on the novel concept of amino acid-amino acid-bond pair unit (AABPU) that allows for an alternative description of proteins, providing valuable information on partial charge, interatomic bonding and hydrogen bond (HB) formation. In general, our results show that the S-protein mutations for different variants foster an increased positive partial charge, alter the interatomic interactions, and disrupt the HB networks. We conclude by outlining a roadmap for future computational research of biomolecular virus-related systems.

Function of Anti-CoV Structure Using INH [1-6]- Tyr160-Met161-His162 Complex

Coronaviruses (CoVs), positive-stranded RNA viruses, can infect humans and multiple species of animals, cause enteric, respiratory, and central nervous system diseases in many species, and are attractive targets for anti-CoV drug design through a pivotal role in viral gene expression and replication through the proteolytic processing of replicase polyproteins. In this work, it has been investigated the junction of six inhibitors including N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide (INH1), NSC 158362 (INH2), JMF 1586 (INH3), (N-(2-aminoethyl)-1-1ziridine-ethanamine) (INH4), [(Z)-1-thiophen-2-ylethylideneamino]thiourea (INH5), and Vanillinbananin (INH6) to coronavirus by forming the complexes of inhibitor-CoV through the hydrogen bonding using the physicochemical properties of the heat of formation, Gibbs free energy, electronic energy, the charge distribution of active parts in the hydrogen bonding, NMR estimation of inhibitor jointed to the database amino acids fragment of Tyr-Met-His as the selective zone of the CoV, positive frequency and intensity of different normal modes of these structures. The theoretical calculations were done at various levels of theory to gain more accurate equilibrium geometrical results. A comparison of these structures with two configurations provides new insights for the design of substrate-based inhibitors targeting CoV. This indicates a feasible model for designing wide-spectrum inhibitors against CoV-associated diseases. The structure-based optimization of these structures has yielded two more efficacious lead compounds, N and O atoms, through forming the hydrogen bonding (H-bonding) with potent inhibition against CoV (Tyr160-Met161-His162), which has been abbreviated as TMH in this work.

Rhamnetin is a better inhibitor of SARS-CoV-2 2'-O-methyltransferase than Dolutegravir: a computational prediction

Background: The 2'-O-methyltransferase is responsible for the capping of SARS-CoV-2 mRNA and consequently the evasion of the host's immune system. This study aims at identifying prospective natural inhibitors of the active site of SARS-CoV-2 2'O-methyltransferase (2'-OMT) through an in silico approach. Materials and Method: The target was docked against a library of natural compounds obtained from edible African plants using PyRx - virtual screening software. The antiviral agent, Dolutegravir which has a binding affinity score of -8.5 kcal mol-1 with the SARS-CoV-2 2'-OMT was used as a standard. Compounds were screened for bioavailability through the SWISSADME web server using their molecular descriptors. Screenings for pharmacokinetic properties and bioactivity were performed with PKCSM and Molinspiration web servers respectively. The PLIP and Fpocket webservers were used for the binding site analyses. The Galaxy webserver was used for simulating the time-resolved motions of the apo and holo forms of the target while the MDWeb web server was used for the analyses of the trajectory data.

Crystal structure of baricitinib, C16H17N7O2S

The crystal structure of baricitinib has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional techniques. Baricitinib crystallizes in space group I2/a (#15) with a = 11.81128(11), b = 7.06724(6), c = 42.5293(3) Å, β = 91.9280(4)°, V = 3548.05(5) Å3, and Z = 8. The crystal structure is characterized by hydrogen-bonded double layers parallel to the ab-planes. The dimers form a graph set R2,2(8). The sulfone ends of the molecules reside in the interlayer regions. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®).

Intramolecular Hydrogen Bonding Patterns and Conformational Preferences of Ouabain—A Molecule with Cardiotonic and Antiviral Activities

Ouabain is a steroid-glycoside compound that has been used for decades for the treatment of heart diseases, and has also proved effective against several viruses, including coronaviruses;its potentialities against SARS-CoV-2 are currently object of various investigations. The molecule contains eight OH groups, whose mutual positions enable the simultaneous presence of several O−H⋅⋅⋅O intramolecular hydrogen bonds (IHB), although only few with bond length shorter than 2 Å and favourable directionality. Conformers corresponding to different IHB patterns have been calculated at the DFT level of theory, using both the B3LYP and the M062X functionals. Two sets of B3LYP calculations were performed, without and with the Grimme’s dispersion correction, to evaluate the influence of dispersion forces on the estimation of the molecular properties. The results highlight four conformers whose relative energies are sufficiently low to make them potentially responsible for the molecule’s biological activities. They also highlight the influence of the incorporation of correlation effects on the estimation of energetics and other properties. © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.

Hydrogen bonding penalty used for virtual screening to discover potent inhibitors for Papain-Like cysteine proteases of SARS-CoV-2.

The Papain-Like proteases (PLpro) of SARS-CoV-2 play a crucial role in viral replication and the formation of nonstructural proteins. To find available inhibitors, the 3D structure of PLpro of SARS2 was obtained by homologous modelling, and we used this structure as a target to search for inhibitors through molecular docking and MM/GBSA binding free energy rescoring. A novel hydrogen bonding penalty was applied to the screening process, which meanwhile took desolvation into account. Finally, 61 compounds were acquired and 4 of them with IC50 at micromolar level tested in vitro enzyme activity assay, which includes clinical drugs tegaserod. Considering the importance of crystal water molecules, the 4 compounds were re-docked and considered bound waters in the active site as a part of PLpro. The binding modes of these 4 compounds were further explored with metadynamics simulations. The hits will provide a starting point for future key interactions identified and lead optimization targetting PLpro.

Inhibition of main protease enzyme (Mpro) by active compounds in cabya (Piper retrofractum Vahl.) for covid-19 treatment via in silico experiment

Covid-19 is caused by aetiological agent for SARS-CoV-2. The disease has caused pandemic responsible for deaths and economic loss worldwide. Therefore, novel drugs of covid-19 primarily using herbs are urgently needed. Cabya (Piper retrofractum Vahl.) is a popular spice and also traditionally applied for herbal medicines. This study conducted an in silico experiment to screen methanolic active compounds in cabya and test their inhibitory activities against main protease enzyme (Mpro) as receptor of SARS-CoV-2. The in silico approach complied with molecular docking protocols enabling to evaluate performance of the compounds to inhibit Mpro. Two common drugs were used as control, i.e. chloroquine and ivermectin. As the results, molecular docking showed a promising inhibition by active compounds in cabya;in this regard, beta-sitosterol demonstrated the strongest inhibition against Mpro with binding affinity -7,5 kcal/mol, which is better than chloroquine (-4.8 kcal/mol) and close to ivermectin (-8,5 kcal/mol). The interaction resulted from two hydrogen bonds with amino acids ARG A131 and ASP A289 at distance of 15Å and 2,49 Å, respectively. The inhibition site of beta-sitosterol was similar to that of ivermectin. This research revealed the potential use of cabya for covid-19 treatment through restriction of molecular binding between virus and receptor.

Molecular docking and dynamics of phytochemicals from Chinese herbs with SARS-CoV-2 RdRp

The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is causing coronavirus disease 2019 (COVID-19) pandemic. Ancient Chinese herbal formulas are effective for diseases caused by viral infection, and their effects on COVID-19 are currently being examined. To directly evaluate the role of Chinese herbs in inhibiting replication of SARS-CoV-2, we investigated how the phytochemicals from Chinese herbs interact with the viral RNA-dependent RNA polymerase (RdRP). Total 1025 compounds were screened, and then 181compounds were selected for molecular docking analysis. Four phytochemicals licorice glycoside E, diisooctyl phthalate, (-)-medicocarpin, and glycyroside showed good binding affinity with RdRp. The best complex licorice glycoside E/RdRp forms 3 hydrogen bonds, 4 hydrophobic interactions, 1 pair of Pi-cation/stacking, and 4 salt bridges. Furthermore, docking complexes licorice glycoside E/RdRp and diisooctyl phthalate/RdRp were optimized by molecular dynamics simulation to obtain the stable conformation. These studies indicate that they are promising as antivirals against SARS-CoV-2.

Molecular docking and dynamics simulations study of selected phytoconstituents of "Pangi" (Pangium edule Reinw) leaf as anti-SARS-CoV-2

Herbal plants are often used as alternative medicine because they contain active compounds for the treatment of diseases and disorders with minimal side effects, and are easily obtained from the surrounding environment. Some of them have antiviral activity. This study aimed to analyze the potential of phytochemical compounds in the leaf of "pangi" (Pangium edule Reinw) as anti-SARS-CoV-2 using molecular docking study. The drug- and lead-likeness properties of the selected compounds were obtained from the Swiss ADME and admetSAR online server tools. Molecular dynamics (MD) simulation of the selected ligand was carried out to validate the stability of the interaction. The results suggested that pangi leaves contain three compounds with remarkable binding affinities with Mpro (main protease) and RBD (receptor binding domain) were (5.beta.)pregnane-3,20.beta.-diol, 14.alpha.,18.alpha.-[4-methyl-3-oxo-(1-oxa-4-azabutane-1,4-diyl)]-, diacetate (PD), ethyl cholate (EC), and bis(3,5,5-trimethylhexyl) phthalate. Because EC will be metabolized in the body into cholic acid (Cho), this compound was then docked and validated using MD simulation. The compound has the best free binding energy (G) with SARS-CoV-2 (-7.1 kcal/mol with Mpro and -6.0 kcal/mol with RBD). Moreover, the compound is bound strongly to the active cavity of Mpro on Thr24, Thr26, His41, and Cys145 residues. The MM-GBSA calculation showed that the interaction of Cho with Mpro was higher than with RBD. According to the RMSD (root mean square deviation), RMSF (root mean square fluctuation), the radius of gyration (Rg), and intermolecular hydrogen bond (H-bond) analysis obtained from 50 ns MD simulations, Cho formed stable interactions with Mpro and RBD. The finding of this study indicated that Cho showed good anti-SARS-CoV-2 activity. The potential of the compound to inhibit the virus can serve as a starting point in the process of developing COVID-19 therapeutic natural medicine.

Investigation on the impact of potential phytocompounds from Curcuma longa against COVID-19

Background and Objective: COVID-19 is a new viral infectious disease caused by SARS-CoV-2 and there are no vaccines or drugs available to treat this deadly disease. Curcuma longa is a well-known medicinal plant with the antiviral property. So, the present study aims to evaluate the antiviral activity of phytocompounds from Curcuma longa against SARS-CoV-2. Materials and Methods: The phytocompounds from the Curcuma longa were docked with the main protease of SARS-CoV-2 (SARS-CoV-2 Mpro) by Autodock 4.2 to analyze the possibility of inhibiting the SARS-CoV-2 Mpro. Protein-ligand interaction profiler and ligplot+v.1.4.5 were used to analyze the interactions between the ligand and protein molecules. The toxicity and pharmacophore of the phytocompounds were determined by SWISSADME and PharmaGist web server.

Specific anti-SARS-CoV-2 S1 IgY-scFv is a promising tool for recognition of the virus

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread globally, a series of vaccines, antibodies and drugs have been developed to combat coronavirus disease 2019 (COVID-19). High specific antibodies are powerful tool for the development of immunoassay and providing passive immunotherapy against SARS-CoV-2 and expected with large scale production. SARS-CoV-2 S1 protein was expressed in E. coli BL21 and purified by immobilized metal affinity chromatography, as antigen used to immunize hens, the specific IgY antibodies were extracted form egg yolk by PEG-6000 precipitation, and the titer of anti-S1 IgY antibody reached 1:10,000. IgY single chain variable fragment antibody (IgY-scFv) was generated by using phage display technology and the IgY-scFv showed high binding sensitivity and capacity to S1 protein of SARS-CoV-2, and the minimum detectable antigen S1 protein concentration was 6 ng/µL. The docking study showed that the multiple epitopes on the IgY-scFv interacted with multiple residues on SARS-CoV-2 S1 RBD to form hydrogen bonds. This preliminary study suggests that IgY and IgY-scFv are suitable candidates for the development of immunoassay and passive immunotherapy for COVID-19 to humans and animals.

In Silico Identification of New Anti-SARS-CoV-2 Agents from Bioactive Phytocompounds Targeting the Viral Spike Glycoprotein and Human TLR4

Background: The recent outbreak of novel coronavirus disease (COVID-19) pandemic caused by SARS-CoV-2 has posed a tremendous threat to mankind. The unavailability of a specific drug or vaccine has been the major concern to date. Spike (S) glycoprotein of SARS-CoV-2 plays the most crucial role in viral infection and immunopathogenesis, and hence this protein appears to be an efficacious target for drug discovery. Objective: The objective of this study was to identify potent bioactive phytocompound that can target viral spike (S) glycoprotein and human TLR4 to reduce immunopathological manifestations of COVID- 19. Methods: A series of thirty (30) bioactive phytocompounds, previously documented for antiviral activity, were theoretically screened for their binding efficacy against key proteins related to the pathogenesis of SARS-CoV-2, namely viral spike (S) glycoprotein, and human TLR4. MD simulation was employed to verify the postulations of molecular docking study, and further ADME analysis was performed to predict the most effective one. Results: Studies hypothesized that two new phytochemicals, viz. cajaninstilbene acid (-8.83 kcal/mol) and papaverine (-5.81 kcal/mol), might be the potent inhibitors of spike glycoprotein with stout binding affinity and favourable ADME attributes. MD simulation further ratified the stability of the docked complexes between the phytochemicals and S protein through strong hydrogen bonding. Our In Silico data also indicated that cajaninstilbene acid and papaverine might block human TLR4, which could be useful in mitigating SARS-CoV-2-induced lethal proinflammatory responses. Conclusion: Experimental data collectively predict cajaninstilbene acid as the potential blocker of S protein which may be used as an anti-viral against COVID-19 in the future. However, further experimental validations alongside toxicological detailing are needed for claiming the candidature of these molecules as future anti-corona therapeutics.

Caffeic acid derivatives and polymethoxylated flavonoids from cat's whiskers (Orthosiphon stamineus) form stable complexes with SARS-CoV molecular targets: an in silico analysis

Cat's whiskers or the 'misai kucing' is an herbal plant native to the Southeast Asian region. The polyphenol enriched leaf extract contains numerous medicinal properties of major pharmaceutical interest. In this study, selected cat's whiskers polyphenols were screened computationally to predict the minimum binding affinities with severe acute respiratory syndrome coronavirus (SARS-CoV) molecular targets. Molecular docking analysis showed that the caffeic acid derivatives and polymethoxylated flavonoids from cat's whiskers bound stably to the binding pocket regions of SARS-CoV molecular targets at - 4.2 to - 7.1 kcal/mol. Furthermore, these cat's whiskers polyphenol-bound SARS-CoV complexes were held fairly strongly by hydrophobic interactions, hydrogen bonds, and electrostatic interactions at various extents.

Anti-inflammatory potential of λ-carrageenan by inhibition of IL-6 receptor: in silico study

In some cases, the immune system in COVID-19 patients leads to the release of excess cytokine production (cytokine storm), which will potentially develop into pneumonia. Interleukin 6 (IL-6) plays the role of pro-inflammatory cytokine, it is a receptor mediated signalling system. Macroalgae is well known as a source of valuable bioactive substances with potential biological activities. Among them is the sulphated polysaccharide lambda-carrageenan λ-CGN which has been reported as an anti-inflammatory agent. However, its mechanism of action against IL-6 production is currently unknown. This study aims to predict potential molecular mechanisms of λ-CGN chemical compound against IL-6 expression through in silico study. Chemical compound of λ-CGN and target protein in this study were obtained from the pubchem and protein data bank (PDB). The molecular docking prediction was conducted with PyRx software, the result is λ-CGN compound showing strong binding energy to bind target protein IL-6 receptor with the value of -5.9 kcal/mol. Based on the results of in silico study, the sulphated polysaccharide λ-CGN potentially inhibits IL-6R expression by binding ligand pocket with six conventional hydrogen bonds (amino acid residus: His256, His 257, Trp 219, Arg 231, and Asp 221) and two carbon hydrogen bonds (amino acid residus: THR 218 and GLN 220). Binding with these amino acid residues potentially contributes to IL-6 receptor structural change which could result in functional change. Hence, further studies related to in vitro and in vivo investigations would be interesting to further understand the inhibitory mechanism of λ-CGN against IL-6.