key: cord-0720583-bok5imdb
authors: Das, Gourab; Das, Troyee; Chowdhury, Nilkanta; Chatterjee, Durbadal; Bagchi, Angshuman; Ghosh, Zhumur
title: Repurposed drugs and nutraceuticals targeting envelope protein: A possible therapeutic strategy against COVID-19
date: 2020-11-13
journal: Genomics
DOI: 10.1016/j.ygeno.2020.11.009
sha: c914a538539338e53afd496963af059c0b68b57c
doc_id: 720583
cord_uid: bok5imdb

COVID-19 pandemic caused by SARS-CoV-2 has already claimed millions of lives worldwide due to the absence of a suitable anti-viral therapy. The CoV envelope (E) protein, which has not received much attention so far, is a 75 amino acid long integral membrane protein involved in assembly and release of the virus inside the host. Here we have used artificial intelligence (AI) and pattern recognition techniques for initial screening of FDA approved pharmaceuticals and nutraceuticals to target this E protein. Subsequently, molecular docking simulations have been performed between the ligands and target protein to screen a set of 9 ligand molecules. Finally, we have provided detailed insight into their mechanisms of action related to the varied symptoms of infected patients.

positively charged, basic amino acids (viz. lysine or arginine) of the protein affix the pore to the negatively charged membrane phospholipids through electrostatic interactions [26] .

It is also suggested that E protein aids in viral assembly, morphogenesis, budding and pathogenesis [27] . Deletion of E protein exhibits formation of significantly crippled viruses though the replication efficiency of the virus is not hampered [28] . Moreover, its role in pathogenesis is implicated through various modes of interactions with the host proteins [29] .

Redistribution of syntenin from nucleus to cytoplasm by E protein results in the activation of p38 MAPK, triggering an over-production of pro-inflammatory cytokines like IL-1β, resulting in edema and other characteristic symptoms of ARDS [30] . Interaction between E and Bcl-xL protein is suspected to induce SARS characteristic lymphopenia [31] .

Knocking down viroporin activity showed reduction in IL-1β production and edema accumulation, restoration of lung epithelial wall integrity and proper functioning of Na + /K + ATPase [32] .

The point mutations in TMD of E-protein are N15A and V25F, could suppress viroporin activity. Particularly V25F results in disruption of pentameric structure which is a crucial evidence for its role in oligomerisation [33] . Interestingly, in a mice model experiment by Nieto-Torres et al., N15A and V25F mutant viruses incorporated compensatory mutations either in these two positions or in close proximities within the TMD domain to render the ion channel active. Those mutations are N15A  A15D and V25F  F25C, L19A, F20 L, F26 L, L27S, T30I, L37R. Only those mice were able to survive and recover which did not incorporate these mutations [32] .

This put forward the immense importance of these amino acids spanning region between 15 th to 37 th position of E-protein in regulating ion channel activity. Thus, we hypothesize that target inhibition of TMD of E-protein, particularly blocking the amino acids playing the roles in viroporin oligomerization could inhibit the pentamer formation and associated pathogenic reactions.

The name of several drugs and phytochemicals have come forward to target against the pentameric structure of E-protein, though very few of them are FDA approved [34] . Here, we aim to combat the spreadability of the virus at the early stage of viral E-Protein synthesis in its monomeric form, before oligomerization and initiation of viroporin pathogenesis.

In this work, we have adopted artificial intelligence (AI) based deep learning and pattern recognition techniques to screen out FDA approved drugs and food supplements which can target E-protein. Our main focus is to target the protein region between 15 th to 37 th J o u r n a l P r e -p r o o f Journal Pre-proof residue, responsible for modulating channel activity. Computational molecular docking based virtual screening was performed thereafter for final selection of the drugs. Further, we have provided detailed insight into their mechanisms of action that could serve as an easy remedial reference for developing therapeutic measures against SARS-CoV-2.

Human SARS CoV E protein sequence has been downloaded from UniProt( ID:P59637) [35] .

It is 76 amino acid residues spanning 26117 bps to 26347 bps of the SARS-CoV genome.

Human SARS-CoV-2 E protein sequence of 75 amino acids (265245-26472, 228 bases) has been downloaded from NCBI protein database (ID: YP_009724392.1) [36] . Protein sequence of the three other structural proteins i.e. Matrix (M), Nucleocapsid (N) and Spike (S) proteins of SARS-CoV and SARS-CoV- 2 2. The region of the protein spanning the amino acid residues 15 to 37 is known to be involved in oligomerization of the protein to make a viable and active pentameric structure necessary for exerting its activity in the host cell. The aforementioned region contains 3 aromatic Phe residues (at position 20, 23 and 26). Therefore, the candidate drug molecule would also need to have aromatic ring structures in order to fit into the three-dimensional space occupied by the said region of E-protein in such a way that oligomerization process would no longer take place. Thus, we have searched for drug molecules containing 2 aromatic rings. The set of drugs obtained after all these screening phases have been considered for subsequent molecular docking.

The screened ligands obtained above were then subjected to computational molecular docking based virtual screening. From the SMILES information of the ligands, their threedimensional structures have been built and then the ligand structure optimization has been performed using Discovery Studio 2.5. We used Autodock VINA [47] for this computational molecular docking. In order to get an unbiased docking result, blind docking has been performed to check the affinity of these ligands towards the zone of protein-protein interactions (PPI).

Here one of the important aspects we have taken care of, while looking into the binding affinity between the ligand and the target protein is the correlation between the binding affinity and docking score. It has been observed that binding affinity between the targeted protein and ligand cannot be judged solely by docking score [48] as they are poorly correlated [49, 50] . Orientation of binding [48] , site of binding [51] and type of binding energy [50] are also important aspects which need to be considered to judge binding affinity.

On the contrary, docking score is highly correlated with the molecular weight of both the ligand and target protein [48] . Hence, higher the molecular weight of the ligand and target protein more will be the docking score and vice-versa.

In this work, we have targeted monomeric structure of E-protein for SARS-CoV-2 constituting 75 amino acids only. For strong interaction with small protein, ligands with length ≤ 100 in terms of SMILES symbol are considered for docking [52, 53] as large molecules may fail to invade the target biologically. As specified above, interaction potential between protein and ligand can be inferred efficiently by considering structure based features instead of ligand based features [54] . Further, Guedes et al., [51] specified that binding affinity depends on the site of binding. In this case, TMD of the E-protein is mostly crucial and responsible for the virulence factor of SARS-CoV-2. We have implemented blind docking, and drugs inhibiting that specific TMD site would reduce the pathogenicity of the virus. The entire workflow is provided in Figure 2 .

Results:

The pairwise nucleotide sequence alignment between SARS-CoV-2 and SARS-CoV has been represented in Figure 3 along with the consensus sequence. Protein sequence J o u r n a l P r e -p r o o f conservation score of all four structural proteins are provided in Table 1 . We observed that E-protein shares the highest sequence similarity among all structural proteins when compared between SARS-CoV-2 and SARS-CoV. The details of pairwise alignment of all the structural proteins between the two strains have been provided in Supplementary File SF1. These set of drugs are further screened based on their existing functions, FDA approval and severity of their side effects. Table 3 enlist the full set of drugs which were sent out for docking.

a.

The initial list consisted of 12715 drugs. Among those, 395 were screened as they fulfilled 2

properties (i) Their length is ≤ 100 in terms of SMILES string format and (ii) Their binding score with all alpha carbon atoms as well as with carbon atoms of E-protein spanning between 15-37 th position is ˃85% using IVS2vec model. Subsequent to AI based screening, the drugs are further filtered, based on existing functions correlating with the symptoms of Finally, 18 drugs have been screened by this method ( Table 3) .

E-protein consists of membrane spanning region with long hydrophobic tail. The suitable ligand which can bind to this membrane spanning region needs to have a hydrophobic part.

Drugs having the necessary hydrophobic zone were screened.

Work of Duangjit et al showed that the hydrophobicity of long carbon chain is greater than short carbon chains and the threshold length of it could be fixed to 16 [46] . This led us to filter those drug molecules (with hydrophobic zone) having long aliphatic carbon chain of length ≥ 16.

Further we checked their existing functions, FDA approval status and reported side effects. Based on all these, we filtered out 6 drug molecules shown in Table 3 . These are Docosanol, Vitamin A Palmitate, Ascorbyl Palmitate, Cetalkonium, Octacosanol and Palmidrol. Among them Docosanol have been rejected as it is a topical medication. Ascorbyl Palmitate, Cetalkonium and Palmidrol have also been screened through AI based screening.

Octacosanol and Vitamin A Palmitate are the exclusive set of drugs which got screened through this pattern recognition based criterion.

As TMD of E-protein containing 3 aromatic Phe residues (at position 20, 23 and 26); so the drugs possessing aromatic carbon ring has got the higher probability to bind with Phe amino acid. Based on this property we have selected list of drugs which has 2 or more aromatic carbon rings. Further, imposing the criterion of functionality, FDA approval status and reported side effects lead to the selection of only 1 drug Nafcillin by this procedure. 

From the molecular docking based virtual screening we have found that from the entire list provided in Table 3 Table 4 depicts the cluster-wise list of the ligand molecules along with their docking score. Table 5 denotes the detailed function and mode of action of these 9 drug molecules.

We then tried to identify the residue specificity of the ligands in order to identify the amino acid residues of the E-protein binding most strongly with the ligand atoms. The docking scores of all the 9 ligands are presented in Table 4 . The binding interactions of all the ligands are presented in Supplementary File SF2. 

The known mechanism of action of the screened ligands are discussed below in the perspective of its actions against the main threatening outcome in COVID-19 patients i.e.

Acute Respiratory Distress Syndrome (ARDS) as well as other (mainly) age related risk factors like hypertension, cholesterol etc which has made aged people more vulnerable towards COVID-19 attack. Their detailed mode of action is depicted in Figure 5A .

Nafcillin is a semi synthetic, narrow spectrum antibiotic which is a beta lactamase resistant penicillin [55] . The bactericidal action of penicillin is to inhibit cell wall synthesis due to the presence of beta lactam ring. [56] . However, certain bacteria develop resistance against the beta lactam ring by synthesizing beta lactam inhibitors i.e. beta-lactamase or penicillinase [57] . To combat this resistance, penicillinase resistance drugs are introduced in the market [58] . Currently, Nafcillin is being used in the treatment of penicillinase producing staphylococcal species particularly methicillin sensitive staphylococcus aureus (MSSA)[59].

Nafcillin is also being used to treat non specific lower respiratory tract infection as well as community-acquired pneumonia (CAP) [60] . Nafcillin is not known to cause life threatening adverse side effects and in our analysis, it shows the highest binding affinity with the TMD domain of monomeric E-protein. Thus, Nafcillin can be taken into consideration for redirecting its purpose for the treatment of SARS-CoV-2 infection as it could also combat bacterial co-infection in a COVID patient which produce the same symptoms as seen in

Nabumetone is an FDA approved non selective anti inflammatory drug (NSAID) which is being used for its anti inflammatory and anti pyretic effects [61] . It is a prodrug which goes though biotransformation within the liver to produce the active component, 6-methoxy-2naphthylacetic acid (6MNA) [62] , that inhibits the synthesis of prostaglandins by acting on Cyclooxygenase (COX) I and II [63] . Prostaglandins are responsible for initiating fever by signalling the hypothalamus to increase body temperature [64] . Prostaglandin also acts as inflammatory mediator acting on blood vessels to promote inflammatory response [65, 66] .

NSAIDs mediate anti-inflammatory effect by preventing vasodilation, reducing capillary permeability and cytokine release from endothelial cells [67] . Altogether, these effects impede the migration of immunocompetent cells the site of injury thereby preventing uncontrolled immune system activation and inflammation [68] (Figure5A) .

During the initial phase of COVID-19, we see the activation of uncontrolled immune response where leukocytes are recruited all over the body [69] . This is followed by an immunosuppression state with death of T and B cells further exacerbating the situation [70] .

Permeability of the blood capillaries, lining the lung alveolar wall increases, causing fluids to leak inside, resulting in pulmonary edema and ARDS [71] . Literature evidences suggest that such situation is triggered by the viral E-protein [32] . Hence, anti-inflammatory agent Nabumetone, by targeting on the monomeric E-protein can hamper its formation of functional pentameric form which in turn could be beneficial in lowering the state of uncontrolled immune response. Although reported to cause less nephrotoxicity and Gastro intestinal (GI) toxicity than other NSAIDs, it still produce considerable side effects and is prescribed to be used by caution particularly for people with heart or kidney condition, high blood pressure and complications arising from thrombosis [72, 73] .

Octacosanol is the main component of plant extracted natural wax and is a low-molecularweight primary aliphatic alcohol [74] . Its role is mainly investigated for the treatment of

Parkinson's disease [75] . It is approved as Nutraceuticals by FDA and is marketed as the main component of Policosanol (PC), a generic term for natural mixture of primary alcohols isolated originally from sugarcane wax [76] . The first PC supplement produced by Dalmer

Laboratories in La Habana, Cuba [77] has been approved as a medication for lowering total cholesterol (TC) and breaking down low density lipoprotein cholesterol (LDL-C) in more than 25 countries including India(Trade name: Zetanol) [78] . It is known to lower cholesterol levels by inducing phosphorylation of AMPK and reducing the activity of HMG-CoA reductase, which is one of the key component of cholesterol biosynthesis [79] . It is also said to increase efflux of tissue LDL by High Density Lipoprotein(HDL) via reverse cholesterol transport pathway and resulting in bigger HDL particles by inhibiting the activity cholesteryl ester transfer protein(CETP) [80, 81] . Bigger HDL particles are postulated to exert more protective function in comparison to total HDL particles [82] .

COVID-19 is known to severely affect the elderly population. People with atherosclerosis and higher cholesterol levels are more vulnerable to severe symptoms [83] . Cholesterol is an essential component for cell membrane structural makeup [84] . Synthesized by the liver, cholesterol is transported via bloodstreams packed within lipoprotein particles to various organs including lungs [85, 86] . LDL is the major blood cholesterol carrier [87] . When LDL levels are high, organs could no longer take up the excess LDLs. They are then oxidised and engulfed by macrophages, get deposited along the arterial wall resulting in plaque formation (atherosclerosis) which increases the risk of stroke and heart attacks [88] . Moreover excess cholesterol in the lung is transported out via ABCA1 efflux pump back to the liver for recycling [89] . This mechanism of effluxion is inhibited during chronic inflammation and reduced with age causing macrophage rich cholesterol to deposit around tissue periphery resulting in increase tissue cholesterol [90, 91] . SARS-CoV-2 uses Spike(S) protein to enter within the host cell cytosol by binding to surface receptor angiotensin-converting enzyme II (ACE2) followed by cleavage of S protein with host proteases [92] . A recent work by Wang et al pointed that increased tissue cholesterol deposits with age can provide more viral entry points by trafficking and concentrating ACE2 as well as host proteases within lipid raft [93] .

Hence, Octacosanol can be utilized both as a tissue cholesterol lowering agent to reduce risk of viral entry beside its repurposed role to inhibit E-protein oligomerization.

Cinametic acid is an FDA approved food additive, mainly obtained from oil of cinnamon and other plant sources [94] . Among the many therapeutic functions of cinnamic acid, one of its role has also been linked to inhibit angiotensin-converting enzyme (ACE) [95] . ACE converts Angiotensin (Ang) I to Ang II. [96] Ang II is responsible for constricting blood vessels and increase blood pressure or hypertension, one of the risk factors for COVID-19 via binding to Angiotensin1 Receptor(AT1R) and activating a cascade of signalling pathways [97, 98] (shown in Figure5A) . Role of Cinametic acid in inhibiting ACE will hamper conversion of Ang I to Ang II which can reduce hypertension. Further, Ang II gets converted to Ang-(I-VII) J o u r n a l P r e -p r o o f by ACE2 in the absence of ACE [99] . Ang(I-VII) has a protective role in the system as it binds to Mas1R receptor and helps in attenuating inflammation and fibrosis related lung injury.

Moreover, this engagement of ACE2 in AngII conversion could in turn decrease the number of free tissue ACE2 for binding of SARS-CoV-2 spike proteins proposed by South et al [100] .

Lauric acid/Dodecanoic acid, major source of which is coconut, can also be found in other plants [101] . It is a medium chain saturated fatty acid [102] . It can also be found in cow, goat and human breast milk [103] . Inside the body, lauric acid gets converted to the biologically active compound Monolaurin which is known for exerting antimicrobial activity [104] , has Ascorbyl palmitate is an FDA approved small molecule. Mainly, it is a fat soluble form of Vitamin C formed by the ester of ascorbic acid and palmitic acid [106] . Being an amphipathic molecule, it has an advantage of being more stable and easily enters into cell membranes [107] . Within human red blood cells, ascorbyl palmitate can exhibit protective property against oxidative damage by free radicals [108] (Figure5A) . The pathophysiological processes involved in COVID-19 can be linked to oxidative stress which increases with age [109] . Particularly, deprivation of antioxidant mechanisms is pivotal for viral replication and proliferation [110] . Generation of high level of Reactive Oxygen species during viral infection can lead to oxidative damage of cells as a result of increased inflammation [111] .

The role of E-protein in activating inflammasome pathway has already been discussed in the introduction. Hence, ascorbyl palmitate which targets E-protein can be a great boost to the immune system not only by reducing oxidative stress but also by enhancing phagocytosis, chemocytosis and interferon production.

Palmidrol / palmitoylethanolamide(PEA) has been initially identified in egg yolk. PEA is a natural fatty acid amide synthesized locally in animal and human tissues from the most common fatty acid source palmitic acid [112] . PEA is known to act locally and is produced when needed thus maintaining tight balance between production and breakdown [113] . PEA is known to be involved in the endocannabinoid system due to its affinity for the novel J o u r n a l P r e -p r o o f orphan cannabinoid receptors GPR55 and GPR119 [114, 115] . In addition to its anti cancer, anti epileptic and neuroprotective properties, PEA is widely known to relieve inflammation associated with respiratory infections such as influenza [116] . Influenza is characterized by the production of pro inflammatory cytokines such as IL-6, IL-10 and TNF(Tumor Necrosis

Factor)-α [117, 118] . PEA is known to lessen the production of inflammatory cytokines by acting as the agonist of PPAR-α receptor and reduces the expression of NF-κβ [119] (Figure5A). It is also responsible for shifting the activated mast cells to the resting state by preventing mast cell migration and release of mast cell mediators like histamine through degranulation [120] . Thus, PEA can combat inflammation through various modes of action and has been found advantageous for treating respiratory viral infections for its minimal side effects and promising efficacy. Currently, PEA is available as a FDA approved nutraceutical under trade name PeaPure and is marketed under the trade name Nomast in Spain and Italy for special medical purposes [121] . These properties along with its capability to inhibit E protein oligomerization makes it a potential nutraceutical to fight against COVID 19.

Salmeterol is a long-acting beta2-adrenergic agonist approved by FDA for treatment of asthma and COPD or high altitude pulmonary edema by stimulating beta2-adrenoceptors predominant in the bronchial smooth muscles [122] . beta2 receptor coupled to the Gs protein, when activated, catalyse the formation of cyclic adenosine monophosphate (cAMP) and activate protein kinase A(PKA), thus inactivating myosin light-chain kinase [123] (Figure5A). This results in dilation of bronchioles and proper passage of air through lung airways which gets obstructed and narrowed due to the accumulation of pus, swelling of alveolar wall linings muscle spasms [124] . These would otherwise lead to shortness of breath, difficulty in breathing, cough and congestion [125] . Such manifestations are also observed among COVID-19 patients which is caused by E-protein and thus Salmeterol which can target E-protein have a high potential to be used for anti viral therapy for COVID- 19 . Salmeterol can also prevent air passage narrowing induced by mast cell released histamine [126] . However, beta2-adrenergic receptors are also found to be present in heart to some extent and thus salmeterol is advised to be administered with caution to patients which could otherwise lead up to undesirable cardiac effects [127] .

Guaifenesin is an FDA approved over the counter(OTC) or non prescription expectorant for treatment of cough and common cold [128] . It aids in the clearance of mucous and other respiratory tract secretion by increasing the volume of trachea and bronchi and reducing mucus viscosity which would otherwise lead to congestion, chronic bronchitis and COPD which are commonly seen in ARDS. Hereby, the action of Guaifenesin result in more productive cough [129] , thus combating the condition of ARDS. This is also expected to J o u r n a l P r e -p r o o f happen if administered to COVID-19 patients as it has the potential to disrupt the formation of the pentameric structure of E-protein which causes ARDS. It is a relatively safe drug to use though not recommended for children below the age of six [130] .

The overall discussion above regarding the known mechanism of action of the concern was also to check the severity of the adverse side effects of these drugs. Hence, second phase of screening was done based on these criteria and selected drugs were utilized for blind docking with the SARS-CoV-2 E-protein to obtain unbiased results in the third phase. Although there exists lack of scoring function which justifies the binding affinity between the ligand and the target protein universally [131] , we have considered orientation of binding, site of binding and type of binding energy along with docking score to judge the binding affinity between them. Hereby, we have come up finally with 9 ligand molecules which has been found to be grouped into three distinct clusters, where ligands in cluster 1 and 2 interacts with the concerned amino acid residues in the zone of interest and those in 

Understanding the emerging coronavirus: what it means for health security and infection prevention

The SARS-CoV-2 outbreak: What we know

SARS-CoV-2: an Emerging Coronavirus that Causes a Global Threat

Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection

Virological assessment of hospitalized patients with COVID-2019

The molecular biology of SARS coronavirus

Genome Composition and Divergence of the Novel Coronavirus (2019-nCoV) Originating in China

Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response

The coronavirus nucleocapsid is a multifunctional protein

Genotype and phenotype of COVID-19: Their roles in pathogenesis

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

Drug targets for COVID-19 therapeutics: Ongoing global efforts

In silico studies on therapeutic agents for COVID-19: Drug repurposing approach

An in-silico evaluation of different Saikosaponins for their potency against SARS-CoV-2 using NSP15 and fusion spike glycoprotein as targets

Repurposing approved drugs as inhibitors of SARS-CoV-2 Sprotein from molecular modeling and virtual screening

Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach. Front Immunol

Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silico study for drug development

Computational evaluation of major components from plant essential oils as potent inhibitors of SARS-CoV-2 spike protein

Exceptional flexibility in the sequence requirements for coronavirus small envelope protein function

Conductance and amantadine binding of a pore formed by a lysineflanked transmembrane domain of SARS coronavirus envelope protein

The E Protein Is a Multifunctional Membrane Protein of SARS-CoV

Structure of a conserved Golgi complex-targeting signal in coronavirus envelope proteins

Coronavirus E protein forms ion channels with functionally and structurally-involved membrane lipids

Structure and inhibition of the SARS coronavirus envelope protein ion channel

Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Ion Channel Activity Promotes Virus Fitness and Pathogenesis

Coronavirus envelope protein: current knowledge

Generation of a replication-competent, propagation-deficient virus vector based on the transmissible gastroenteritis coronavirus genome

Emerging theme: cellular PDZ proteins as common targets of pathogenic viruses

The PDZ-binding motif of severe acute respiratory syndrome coronavirus envelope protein is a determinant of viral pathogenesis

Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors

Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis

Protein-Protein Interactions of Viroporins in Coronaviruses and Paramyxoviruses: New Targets for Antivirals? Viruses, 2015

In-silico approaches to detect inhibitors of the human severe acute respiratory syndrome coronavirus envelope protein ion channel

UniProt: the universal protein knowledgebase

Database resources of the National Center for Biotechnology Information

The Jalview Java alignment editor

Data, disease and diplomacy: GISAID's innovative contribution to global health. Glob Chall

SWISS-MODEL: An automated protein homology-modeling server

ChEMBL: a large-scale bioactivity database for drug discovery

The ChEMBL database in 2017

IVS2vec: A tool of Inverse Virtual Screening based on word2vec and deep learning techniques. Methods

Mol2vec: Unsupervised Machine Learning Approach with Chemical Intuition

Efficient Estimation of Word Representations in Vector Space

The PDBbind database: collection of binding affinities for proteinligand complexes with known three-dimensional structures

Role of the charge, carbon chain length, and content of surfactant on the skin penetration of meloxicam-loaded liposomes

AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading

Is It Reliable to Take the Molecular Docking Top Scoring Position as the Best Solution without Considering Available Structural Data? Molecules

A critical assessment of docking programs and scoring functions

Assessment of programs for ligand binding affinity prediction

Receptor-ligand molecular docking

Increasing the range of drug targets: interacting peptides provide leads for the development of oncoprotein inhibitors

Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors

Towards accurate high-throughput ligand affinity prediction by exploiting structural ensembles, docking metrics and ligand similarity

New antistaphylococcal antibiotics. Comparative in vitro and in vivo activity of cephalothin, nafcillin, cloxacillin, oxacillin, and methicillin

Bacterial resistance to beta-lactam antibiotics: crystal structure of beta-lactamase from Staphylococcus aureus PC1 at 2.5 A resolution

The role of beta-lactamase in staphylococcal resistance to penicillinase-resistant penicillins and cephalosporins

Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillin-susceptible Staphylococcus aureus bacteremia

Evaluation of the efficacy and safety of outpatient parenteral antimicrobial therapy for infections with methicillin-sensitive Staphylococcus aureus

A reappraisal of its pharmacology and therapeutic use in rheumatic diseases

Simultaneous analysis of naproxen, nabumetone and its major metabolite 6-methoxy-2-naphthylacetic acid in pharmaceuticals and human urine by high-performance liquid chromatography

Inhibitory effects of nabumetone, a cyclooxygenase-2 inhibitor, and esculetin, a lipoxygenase inhibitor, on N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats

Prostaglandin E levels in third ventricular cerebrospinal fluid of rabbits during fever and changes in body temperature

Prostaglandins, arachidonic acid, and inflammation

Hypoxia releases a vasoconstrictor substance from the canine vascular endothelium

NSAIDs, coxibs, CINOD and H2S-releasing NSAIDs: what lies beyond the horizon. Dig Liver Dis

Nonsteroidal Anti-inflammatory Drugs (NSAIDs), in StatPearls. 2020: Treasure Island (FL)

Coronavirus disease 2019 (COVID-19) and anti-rheumatic drugs

Pathological alteration and therapeutic implications of sepsis-induced immune cell apoptosis

Treatment for severe acute respiratory distress syndrome from COVID-19

Low direct cytotoxicity of nabumetone on gastric mucosal cells

Mechanisms of Damage to the Gastrointestinal Tract From Nonsteroidal Anti-Inflammatory Drugs

Health Benefits of Octacosanol and Other Long-Chain Aliphatic Fatty Alcohols from Plants

Anti-parkinsonian effects of octacosanol in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-treated mice

Policosanol contents and compositions of wheat varieties

Policosanol: a new treatment for cardiovascular disease

Clinical Strategies in the Testing of Thyroid Function

Policosanol Attenuates Cholesterol Synthesis via AMPK Activation in Hypercholesterolemic Rats

Improvement and Enhancement of HDL and Clinical Applications

Policosanol: Extraction and biological functions

The metabolic pathways of high-density lipoprotein, lowdensity lipoprotein, and triglycerides: a current review

Familial hypercholesterolaemia and COVID-19: triggering of increased sustained cardiovascular risk

The Chemical Potential of Plasma Membrane Cholesterol: Implications for Cell Biology

Anatomy and Physiology

Apolipoprotein E: cholesterol transport protein with expanding role in cell biology

LDL-cholesterol transport to the endoplasmic reticulum: current concepts

Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses

Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study

Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes

A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells

The role of high cholesterol in age-related COVID19 lethality. bioRxiv

Antioxidant and antimicrobial activities of cinnamic acid derivatives

Anti-obesity and cardioprotective effects of cinnamic acid in high fat diet-induced obese rats

A genetic variant of ACE increases cell survival: a new paradigm for biology and disease

Association between angiotensin II type 1 receptor gene polymorphism and essential hypertension: the Ohasama Study

The Role of beta-Arrestin Proteins in Organization of Signaling and Regulation of the AT1 Angiotensin Receptor

COVID-19 and the elderly: insights into pathogenesis and clinical decision-making

Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic

The Properties of Lauric Acid and Their Significance in Coconut Oil

Lauric acid is a medium-chain fatty acid, coconut oil is a medium-chain triglyceride

Long-chain polyunsaturated fatty acid content in Dutch preterm breast milk; differences in the concentrations of docosahexaenoic acid and arachidonic acid due to length of gestation

In Vitro Effects of Monolaurin Compounds on Enveloped Rna and DNA Viruses

Inactivation of enveloped viruses and killing of cells by fatty acids and monoglycerides

Stability of ascorbyl palmitate in topical microemulsions

Skin protection against ultraviolet induced free radicals with ascorbyl palmitate in microemulsions

Ascorbate 6-palmitate protects human erythrocytes from oxidative damage. Free Radic Biol Med

Oxidative Stress as Key Player in Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection

Redox Biology of Respiratory Viral Infections. Viruses

Respiratory Viral Infections and Subversion of Cellular Antioxidant Defenses

THE IDENTIFICATION OF N-(2-HYDROXYETHYL)-PALMITAMIDE AS A NATURALLY OCCURRING ANTI-INFLAMMATORY AGENT

Endogenous Cannabinoids: Structure and Metabolism

The search for the palmitoylethanolamide receptor

Receptors for acylethanolamides-GPR55 and GPR119

Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold

Intensive cytokine induction in pandemic H1N1 influenza virus infection accompanied by robust production of IL-10 and IL-6

Molecular pathways in virus-induced cytokine production

PPAR-alpha in cutaneous inflammation

Effects of palmitoylethanolamide on immunologically induced histamine, PGD2 and TNFalpha release from canine skin mast cells

Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold

The long-acting beta2-agonist salmeterol xinafoate: effects on airway inflammation in asthma

Targeting G protein-coupled receptor signaling in asthma

A comparison of the effects of oral montelukast and inhaled salmeterol on response to rescue bronchodilation after challenge

The activity of pulmonary stretch receptors during bronchoconstriction, pulmonary oedema, atelectasis and breathing against a resistance

Salmeterol inhibits anaphylactic histamine release from guineapig isolated mast cells

Cardiac effects of formoterol and salmeterol in patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia

Inhibition of cough-reflex sensitivity by benzonatate and guaifenesin in acute viral cough

Role of guaifenesin in the management of chronic bronchitis and upper respiratory tract infections

The National Cancer Policy Summit: Opportunities and Challenges in Cancer Research and Care

Can we trust docking results? Evaluation of seven commonly used programs on PDBbind database

We are grateful to Council of Scientific and Industrial Research (CSIR) and Department of Science and Technology (DST) for financial support. We also thank University of Kalyani for their constant support to carry out this research work.

The key highlights of the paper are as follows: This work focuses on 75 amino acid long integral membrane Envelope (E) Protein as the target. It is one of the four structural proteins of the SARS-CoV-2 virus and is the most conserved among all. Because of this conserved nature, drugs targeting E protein would have long term efficacy.  We implemented artificial intelligence (AI) and pattern recognition techniques for initial screening, keeping in mind the small size of the protein and hydrophobic nature of our zone of interest.  Next level of screening was based on their (a) existing functions (i.e. whether they can subdue SARS-CoV2 induced symptoms especially in the context of the function of E-protein), (b) FDA approval status and (c) severity of the reported side effects.  Finally, blind molecular docking simulation has been done and 9 ligand molecules have been screened. We have also provided a detailed insight into the mechanisms of action of these final selected 9 drugs related to the varied symptoms of infected patients.  These FDA approved drug and food supplements can not only prevent E protein oligomerization but can also combat several SARS-Cov2 induced symptoms.J o u r n a l P r e -p r o o f