Interpretation of SARS-CoV-2 behaviour on different substrates and denaturation of virions using ethanol: an atomic force microscopy study

Coronavirus (SARS-CoV-2) is a respiratory infection virus that was first detected in Wuhan, China. The virus causes COVID-19 disease and the outbreak was recognised as a pandemic by the World Health Organization (WHO) in March 2020. SARS-CoV-2 virion was first imaged using cryo-electron microscopy by the Chinese Center for Disease Control and Prevention (CDC). Atomic Force Microscopy is a unique technique that can allow imaging of biomolecules under different conditions. In this work, we used Atomic Force Microscopy to characterize SARS-CoV-2 on tissue culture polystyrene (TCPS) and glass coverslip surfaces. We isolated SARS-CoV-2 and drop casted it on coverslip glass and tissue culture polystyrene surfaces. We analyzed height profiles, density, and aggregation behavior of the virion on glass and polystyrene surfaces. We observed the coffee ring effect on the drop casted samples and close packing of virions near the coffee rings on both surfaces with relatively higher virion distribution on the tissue culture polystyrene (TCPS) substrates. We compare virion agglomeration on the two types of surfaces. Finally, we applied ethanol disinfectant to virions on the surface to visualize the effect of ethanol and image the ultrastructure of SARS-CoV-2.

We studied the density and aggregation behavior of virions on TCPS and glass substrates, surface functionality, coffee ring effect on both surfaces and the effect of ethanol-based disinfectant on the virion structure using atomic force microscopy.     

Computational estimation of potential inhibitors from known drugs against the main protease of SARS-CoV-2

The coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide recently, leading to global social and economic disruption. Although the emergently approved vaccine programs against SARS-CoV-2 have been rolled out globally, the number of COVID-19 daily cases and deaths has remained significantly high. Here, we attempt to computationally screen for possible medications for COVID-19 via rapidly estimating the highly potential inhibitors from an FDA-approved drug database against the main protease (Mpro) of SARS-CoV-2. The approach combined molecular docking and fast pulling of ligand (FPL) simulations that were demonstrated to be accurate and suitable for quick prediction of SARS-CoV-2 Mpro inhibitors. The results suggested that twenty-seven compounds were capable of strongly associating with SARS-CoV-2 Mpro. Among them, the seven top leads are daclatasvir, teniposide, etoposide, levoleucovorin, naldemedine, cabozantinib, and irinotecan. The potential application of these drugs in COVID-19 therapy has thus been discussed.

Approved drugs predicted to interact with critical residues in the substrate-binding site of SARS-CoV-2 Mpro can be promising inhibitors.     

In silico study of natural compounds from sesame against COVID-19 by targeting Mpro,PLpro and RdRp

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

Natural products and traditional medicine products with known safety profiles are a promising source for the discovery of new drug leads.     

Quinazoline-Schiff base conjugates: in silico study and ADMET predictions as multi-target inhibitors of coronavirus (SARS-CoV-2) proteins

The 2019 coronavirus (COVID-19) pandemic is spreading worldwide, with a dramatic increase in death without any effective therapeutic treatment available up to now. We previously reported quinazoline-trihydroxyphenyl Schiff base conjugates as phosphodiesterase 4B (PDE 4B) inhibitors (an enzyme that plays an essential role in the early stages of COVID-19 pneumonia). Additionally, the structural similarity between these conjugates and identified anti-severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 flavonoids inspired us to in silico study their possible binding interactions with essential SARS-CoV-2 proteins. Thus, this study provides an insight into the potential bindings between quinazoline-Schiff base conjugates and SARS-CoV-2 proteins, including spike glycoprotein (SGp), main protease (M^pro) and RNA-dependent RNA polymerase (RdRp), to offer an opportunity to find an effective therapy. Besides this, based on the role that COVID-19 plays in iron dysmetabolism, the conjugate trihydroxyphenyl moiety should be reconsidered as an iron chelator. Moreover, molecular dynamics simulations of quinazoline derivative Ic bound to the mentioned targets were carried out. Finally, ADMET calculations were performed for the studied compounds to predict their pharmacokinetic profiles.

Design of 2-phenylquinazolin-4(3H)one-trihydroxyphenyl Schiff base conjugates as COVID-19 therapy.     

Natural coumarins as potential anti-SARS-CoV-2 agents supported by docking analysis

COVID-19 is a global pandemic first identified in China, causing severe acute respiratory syndrome. One of the therapeutic strategies for combating viral infections is the search for viral spike proteins as attachment inhibitors among natural compounds using molecular docking. This review aims at shedding light on the antiviral potential of natural products belonging to the natural-products class of coumarins up to 2020. Moreover, all these compounds were filtered based on ADME analysis to determine their physicochemical properties, and the best 74 compounds were selected. Using virtual-screening methods, the selected compounds were investigated for potential inhibition of viral main protease (Mpro), viral methyltransferase (nsp16/10 complex), viral recognition binding domain (RBD) of S-protein, and human angiotensin-converting enzyme 2 (ACE2), which is the human receptor for viral S-protein targets, using molecular-docking studies. Promising potential results against SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and methyltransferase (nsp16) are presented.

Potential of coumarins against Covid-19.     

Anti-inflammatory,antiallergic and COVID-19 protease inhibitory activities of phytochemicals from the Jordanian hawksbeard: identification,structure–activity relationships,molecular modeling and impact on its folk medicinal uses

On Wednesday 11^th March, 2020, the world health organization (WHO) announced novel coronavirus (COVID-19, also called SARS-CoV-2) as a pandemic. Due to time shortage and lack of either a vaccine and/or an effective treatment, many trials focused on testing natural products to find out potential lead candidates. In this field, an edible and folk medicinal Jordanian plant Crepis sancta (Asteraceae) was selected for this study. Phytochemical investigation of its enriched polyphenolic extract afforded four eudesmane sesquiterpenes (1–4) together with (6S,9R)-roseoside (5) and five different methylated flavonols (6–10). Structure elucidation of isolated compounds was unambiguously determined based on HRESIMS, X-ray crystallography, and exhaustive 1D and 2D NMR experiments. All isolated compounds were assessed for their in vitro anti-inflammatory, antiallergic and in silico COVID-19 main protease (M^pro) inhibitory activities. Among the tested compounds, compounds 5–10 revealed potent anti-inflammatory, antiallergic and COVID-19 protease inhibitory activities. Chrysosplenetin (10) is considered as a promising anti-inflammatory and antiallergic lead structure adding to the phytotherapeutic pipeline. Moreover, its inhibitory activity against SARS-CoV-2 M^pro, supported by docking and molecular dynamic studies, strengthens its potential as a lead structure paving the way toward finding out a natural remedy to treat and/or to control the current COVID-19 pandemic.

On Wednesday 11th March, 2020, the world health organization (WHO) announced novel coronavirus (COVID-19, also called SARS-CoV-2) as a pandemic.     

ACE2 as a potential therapeutic target for pandemic COVID-19

SARS-CoV-2 virus invades the host through angiotensin-converting enzyme 2 (ACE2) receptors by decreasing the ACE2 expression of the host. This disturbs the dynamic equilibrium between the ACE/Ang II/AT1R axis and ACE2/Ang (1–7)/Mas receptor axis. Therefore, the clinically approved drugs belonging to (i) angiotensin converting enzyme (ACE) inhibitors such as captopril, and enalaprilat, (ii) angiotensin-receptor blockers (ARBs) such as losartan, candesartan, olmesartan, azilsartan, irbesartan, and telmisartan and (iii) the combination of ACE inhibitors and ARBs such as losartan with lisinopril and captopril with losartan, and (iv) recombinant ACE2, were studied for their ability to activate ACE2 in different medical conditions including hypertension, inflammation, cardiovascular, renal and lung diseases. These clinically approved drugs were found to activate ACE2 that had been downregulated in different medical conditions including hypertension, inflammation, cardiovascular, renal and lung diseases. Therefore, these drugs may be repurposed to re-activate the downregulated ACE2 of COVID-19 patients. These drugs either alone or in combination may be repurposed as prophylactics and therapeutics against SARS-CoV-2 virus.

SARS-CoV-2 virus invades the host through angiotensin-converting enzyme 2 (ACE2) receptors by decreasing the ACE2 expression of the host.     

Computational methods directed towards drug repurposing for COVID-19: advantages and limitations

Novel coronavirus disease 2019 (COVID-19) has significantly altered the socio-economic status of countries. Although vaccines are now available against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent for COVID-19, it continues to transmit and newer variants of concern have been consistently emerging world-wide. Computational strategies involving drug repurposing offer a viable opportunity to choose a medication from a rundown of affirmed drugs against distinct diseases including COVID-19. While pandemics impede the healthcare systems, drug repurposing or repositioning represents a hopeful approach in which existing drugs can be remodeled and employed to treat newer diseases. In this review, we summarize the diverse computational approaches attempted for developing drugs through drug repurposing or repositioning against COVID-19 and discuss their advantages and limitations. To this end, we have outlined studies that utilized computational techniques such as molecular docking, molecular dynamic simulation, disease–disease association, drug–drug interaction, integrated biological network, artificial intelligence, machine learning and network medicine to accelerate creation of smart and safe drugs against COVID-19.

Different kind of methods utilized in expediting drug repurposing.     

Targeting severe acute respiratory syndrome-coronavirus (SARS-CoV-1) with structurally diverse inhibitors: a comprehensive review

Coronaviruses, which were discovered in 1968, can lead to some human viral disorders, like severe acute respiratory syndrome (SARS), Middle East respiratory syndrome-related (MERS), and, recently, coronavirus disease 2019 (COVID-19). The coronavirus that leads to COVID-19 is rapidly spreading all over the world and is the reason for the deaths of thousands of people. Recent research has revealed that there is about 80% sequence homology between the coronaviruses that cause SARS and COVID-19. Considering this fact, we decided to collect the maximum available information on targets, structures, and inhibitors reported so far for SARS-CoV-1 that could be useful for researchers who work on closely related COVID-19. There are vital proteases, like papain-like protease 2 (PL2pro) and 3C-like protease (3CLpro), or main protease (Mpro), that are involved in and are essential for the replication of SARS coronavirus and so are valuable targets for the treatment of patients affected by this type of virus. SARS-CoV-1 NTPase/helicase plays an important role in the release of several non-structural proteins (nsps), so it is another essential target relating to the viral life cycle. In this paper, we provide extensive information about diverse molecules with anti-SARS activity. In addition to traditional medicinal chemistry outcomes, HTS, virtual screening efforts, and structural insights for better understanding inhibitors and SARS-CoV-1 target complexes are also discussed. This study covers a wide range of anti-SARS agents, particularly SARS-CoV-1 inhibitors, and provides new insights into drug design for the deadly SARS-CoV-2 virus.

Since the coronaviruses that cause COVID-19 and SARS-CoV-1 share 80% structural similarity, we present a comprehensive review of the diverse molecular inhibitors of SARS-CoV-1. This will help to accelerate drug discovery for deadly coronavirus diseases.     

Potential role of medicinal plants and their constituents in the mitigation of SARS-CoV-2: identifying related therapeutic targets using network pharmacology and molecular docking analyses

Since the outbreak of Coronavirus disease (COVID-19) caused by SARS-CoV-2 in December 2019, there has been no vaccine or specific antiviral medication for treatment of the infection where supportive care and prevention of complications is the current management strategy. In this work, the potential use of medicinal plants and more than 16 500 of their constituents was investigated within two suggested therapeutic strategies in the fight against SARS-CoV-2 including prevention of SARS-CoV-2 RNA synthesis and replication, through targeting vital proteins and enzymes as well as modulation of the host''s immunity through production of virulence factors. Molecular docking studies on the viral enzymes 3Clpro, PLpro and RdRp suggested rocymosin B, verbascoside, rutin, caftaric acid, luteolin 7-rutinoside, fenugreekine and cyanidin 3-(6′′-malonylglucoside) as promising molecules for further drug development. Meanwhile, the medicinal plants Glycyrrhiza glabra, Hibiscus sabdariffa, Cichorium intybus, Chrysanthemum coronarium, Nigella sativa, Anastatica hierochuntica, Euphorbia species, Psidium guajava and Epilobium hirsutum were enriched in compounds with the multi-targets PTGS2, IL2, IL1b, VCAM1 and TNF such as quercetin, ursolic acid, kaempferol, isorhamnetin, luteolin, glycerrhizin and apigenin. Enriched pathways of the molecular targets included cytokine–cytokine receptor interaction, TNF signaling pathway, NOD-like receptor signaling pathway, Toll-like receptor signaling pathway, NF-kappa B signaling pathway and JAK-STAT3 signaling pathway which are all closely related to inflammatory, innate and adaptive immune responses. The present study identified natural compounds targeting SARS-CoV-2 for further in vitro and in vivo studies and emphasizes the potential role of medicinal plants in the mitigation of SARS-CoV-2.

Since the outbreak of Coronavirus disease (COVID-19) caused by SARS-CoV-2 in December 2019, there has been no vaccine or specific antiviral medication for treatment of the infection where supportive care and prevention of complications is the current management strategy.     

Revisiting activity of some glucocorticoids as a potential inhibitor of SARS-CoV-2 main protease: theoretical study

The global breakout of COVID-19 and raised death toll has prompted scientists to develop novel drugs capable of inhibiting SARS-CoV-2. Conducting studies on repurposing some FDA-approved glucocorticoids can be a promising prospective for finding a treatment for COVID-19. In addition, the use of anti-inflammatory drugs, such as glucocorticoids, is a pivotal step in the treatment of critical cases of COVID-19, as they can provoke an inflammatory cytokine storm, damaging lungs. In this study, 22 FDA-approved glucocorticoids were identified through in silico (molecular docking) studies as the potential inhibitors of COVID-19''s main protease. From tested compounds, ciclesonide 11, dexamethasone 2, betamethasone 1, hydrocortisone 4, fludrocortisone 3, and triamcinolone 8 are suggested as the most potent glucocorticoids active against COVID-19''s main protease. Moreover, molecular dynamics simulations followed by the calculations of the binding free energy using MM-GBSA were carried out for the aforementioned promising candidate-screened glucocorticoids. In addition, quantum chemical calculations revealed two electron-rich sites on ciclesonide where binding interactions with the main protease and cleavage of the prodrug to the active metabolite take place. Our results have ramifications for conducting preclinical and clinical studies on promising glucocorticoids to hasten the development of effective therapeutics against COVID-19. Another advantage is that some glucocorticoids can be prioritized over others for the treatment of inflammation accompanying COVID-19.

The global breakout of COVID-19 and raised death toll has prompted scientists to develop novel drugs capable of inhibiting SARS-CoV-2.     

Antiviral agents against COVID-19: structure-based design of specific peptidomimetic inhibitors of SARS-CoV-2 main protease

Despite the intense development of vaccines and antiviral therapeutics, no specific treatment of coronavirus disease 2019 (COVID-19), caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently available. Recently, X-ray crystallographic structures of a validated pharmacological target of SARS-CoV-2, the main protease (M^pro also called 3CL^pro) in complex with peptide-like irreversible inhibitors have been published. We have carried out computer-aided structure-based design and optimization of peptidomimetic irreversible α-ketoamide M^pro inhibitors and their analogues using MM, MD and QM/MM methodology, with the goal to propose lead compounds with improved binding affinity to SARS-CoV-2 M^pro, enhanced specificity for pathogenic coronaviruses, decreased peptidic character, and favourable drug-like properties. The best inhibitor candidates designed in this work show largely improved interaction energies towards the M^pro and enhanced specificity due to 6 additional hydrogen bonds to the active site residues. The presented results on new SARS-CoV-2 M^pro inhibitors are expected to stimulate further research towards the development of specific anti-COVID-19 drugs.

Structure-based design of SARS-CoV-2 main protease inhibitors identified hydantoin, benzothiazine and cresol moieties as promising residues of new peptidomimetic inhibitors.     

Understanding the role of galectin inhibitors as potential candidates for SARS-CoV-2 spike protein: in silico studies

The Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) has been rapidly transmitting and leaving its footprints across the globe. Stringent measures like complete lockdown and extensive testing have been employed by many countries to slow it down in its tracks until a viable treatment is found. Therefore, in the current scenario, prompt solutions need to be uncovered to tackle the virus. In the present study, 330 galectin inhibitors were tested against SARS-CoV-2 spike (S) protein with the aid of molecular docking and molecular dynamics. Finally, the binding free energy and contributing energies were calculated for 2 top scoring ligands by using MM–GBSA method. Many of the galectin inhibitors displayed high binding score against the S protein. They were found to bind to the site of contact of S protein to ACE2. Thus, they show promise of disrupting the ACE2–S protein binding and prevent the virus from invading the host cell. Among the ligands screened, TD-139, a molecule currently in Phase IIb clinical trials, was found to be a potential hit. The present study paves the way for in vitro and in vivo testing of galectin inhibitors against SARS-CoV-2. In addition, it warrants a swift examination of TD-139 for treating COVID-19.

Galectin 3 have the potential to inhibit the SARS-CoV-2 spike protein. We validated the studies by docking, MD and MM/GBSA calculations.     

A comprehensive overview of vaccines developed for pandemic viral pathogens over the past two decades including those in clinical trials for the current novel SARS-CoV-2

The unprecedented coronavirus disease 2019 (COVID-19) is triggered by a novel strain of coronavirus namely, Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). Researchers are working around the clock to control this pandemic and consequent waves of viral reproduction, through repurposing existing drugs as well as designing new vaccines. Several countries have hastened vaccine design and clinical trials to quickly address this outbreak. Currently, more than 250 aspirants against SARS-CoV-2 are in progress, including mRNA-replicating or non-replicating viral vectored-, DNA-, autologous dendritic cell-based-, and inactivated virus-vaccines. Vaccines work by prompting effector mechanisms such as cells/molecules, which target quickly replicating pathogens and neutralize their toxic constituents. Vaccine-stimulated immune effectors include adjuvant, affinity, avidity, affinity maturation, antibodies, antigen-presenting cells, B lymphocytes, carrier protein, CD4⁺ T-helper cells. In this review, we describe updated information on the various vaccines available over the last two decades, along with recent progress in the ongoing battle developing 63 diverse vaccines against SARS-CoV-2. The inspiration of our effort is to convey the current investigation focus on registered clinical trials (as of January 08, 2021) that satisfy the safety and efficacy criteria of international wide vaccine development.

We describe updated information on the various vaccines available over the last two decades, along with recent progress in developing 63 diverse vaccines against SARS-CoV-2.     

Comparative assessment of RNA-dependent RNA polymerase (RdRp) inhibitors under clinical trials to control SARS-CoV2 using rigorous computational workflow

The devastating effect of SARS-CoV2 continues and the scientific community is pursuing to find the strategy to combat the spread of the virus. The approach is adapted to target this virus with medicine in combination with existing vaccines. For this, the medications that can specifically inhibit an enzyme essential for viral replication ‘RNA-dependant-RNA polymerase (RdRp)’ of SARS-CoV2 are being developed. RdRp is the enzyme commonly found in all RNA viruses but is absent in humans. There are in total 60 different RdRp inhibitors already under clinical trials for combating other RNA viruses, which are sought to even work for SARS-CoV2. These inhibitors are classified as nucleoside/nucleotide analogues and nonnucleoside/nonnucleotide analogues. In this study, all the known RdRp inhibitors were computationally targeted in the native form and their active form making the use of molecular docking, MM-GBSA and molecular dynamics (MD) simulations to find the top two of each nucleoside/nucleotide analogues and nonnucleoside/nonnucleotide analogues. The results showed ribavirin 5′-triphosphate and favipiravir ribonucleoside triphosphate (favipiravir-RTP) to be the top two nucleotide analogues while pimodivir and dihydropyrazolopyridinone analogue 8d were the top two nonnucleosides/non-nucleotide analogues.

Identifying the inhibitors for RNA-dependant-RNA polymerase (RdRp) of SARS-CoV2.     

Antiviral activities of natural compounds and ionic liquids to inhibit the Mpro of SARS-CoV-2: a computational approach

The recalcitrant spread of the COVID-19 pandemic produced by the novel coronavirus SARS-CoV-2 is one of the most destructive occurrences in history. Despite the availability of several effective vaccinations and their widespread use, this line of immunization often faces questions about its long-term efficacy. Since coronaviruses rapidly change, and multiple SARS-CoV-2 variants have emerged around the world. Therefore, finding a new target-based medication became a priority to prevent and control COVID-19 infections. The main protease (Mpro) is a salient enzyme in coronaviruses that plays a vital role in viral replication, making it a fascinating therapeutic target for SARS-CoV-2. We screened 0.2 million natural products against the Mpro of SARS-CoV-2 using the Universal Natural Product Database (UNPD). As well, we studied the role of ionic liquids (ILs) on the structural stabilization of Mpro. Cholinium-based ILs are biocompatible and used for a variety of biomedical applications. Molecular docking was employed for the initial screening of natural products and ILs against Mpro. To predict the drug-likeness features of lead compounds, we calculated the ADMET properties. We performed MD simulations for the selected complexes based on the docking outcomes. Using MM/PBSA approaches, we conclude that compounds NP-Hit2 (−25.6 kcal mol⁻¹) and NP-Hit3 (−25.3 kcal mol⁻¹) show stronger binding affinity with Mpro. The hotspot residues of Thr25, Leu27, His41, Met49, Cys145, Met165, and Gln189 strongly interacted with the natural compounds. Furthermore, naproxenate, ketoprofenate, and geranate, cholinium-based ILs strongly interact with Mpro and these ILs have antimicrobial properties. Our findings will aid in the development of effective Mpro inhibitors.

The selected natural compounds NP-Hit2, NP-Hit3 and cholinium-based ILs exhibit potential antiviral activity against Mpro of SARS-CoV-2.     

Curcumin to inhibit binding of spike glycoprotein to ACE2 receptors: computational modelling,simulations, and ADMET studies to explore curcuminoids against novel SARS-CoV-2 targets

The recent emergence of the novel coronavirus (SARS-CoV-2) has raised global concern as it is declared a pandemic by the WHO. However, to date, there is no current regimen to mitigate the molecular pathogenesis of SARS-CoV-2 virus. Curcuminoids, bioactive ingredients present in Curcuma longa (turmeric), are known to exhibit diverse pharmacological properties. To the best of our understanding to date, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for the host cellular entry. This is mediated via proteins of SARS-CoV-2, especially the spike glycoprotein receptor binding domain. Accordingly, our primary objective is to thwart virus replication and binding to the host system, leading us to probe curcuminoids efficiency towards key surface drug target proteins using the computational biology paradigm approach. Specifically, fourteen natural curcuminoids were studied for their possibility of inhibiting SARS-CoV-2. We studied their in silico properties towards SARS-CoV-2 target proteins by homology modelling, ADME, drug-likeness, toxicity predictions, docking molecular dynamics simulations and MM-PBSA free energy estimation. Among the curcuminoids docked to the receptor binding domain of SARS-CoV-2 spike glycoprotein, the keto and enol forms of curcumin form strong hydrogen bond interactions with ACE2 binding residues Q493, T501, Y505, Y489 and Q498. Molecular dynamics simulations, free energy binding and interaction energy validated the interaction and stability of the docked keto and enol forms of curcumin.

The significant role of curcumin against SARS-CoV-2 drug targets to thwart virus replication and binding into the host system using the computational biology paradigm approach.     

A phytochemical-based medication search for the SARS-CoV-2 infection by molecular docking models towards spike glycoproteins and main proteases

Identifying best bioactive phytochemicals from different medicinal plants using molecular docking techniques demonstrates a potential pre-clinical compound discovery against SARS-CoV-2 viral infection. The in silico screening of bioactive phytochemicals with the two druggable targets of SARS-CoV-2 by simple precision/extra precision molecular docking methods was used to compute binding affinity at its active sites. phyllaemblicin and cinnamtannin class of phytocompounds showed a better binding affinity range (−9.0 to −8.0 kcal mol⁻¹) towards both these SARS-CoV-2 targets; the corresponding active site residues in the spike protein were predicted as: Y453, Q496, Q498, N501, Y449, Q493, G496, T500, Y505, L455, Q493, and K417; and M^pro: Q189, H164, H163, P168, H41, L167, Q192, M165, C145, Y54, M49, and Q189. Molecular dynamics simulation further established the structural and energetic stability of protein–phytocompound complexes and their interactions with their key residues supporting the molecular docking analysis. Protein–protein docking using ZDOCK and Prodigy server predicted the binding pose and affinity (−13.8 kcal mol⁻¹) of the spike glycoprotein towards the human ACE2 enzyme and also showed significant structural variations in the ACE2 recognition site upon the binding of phyllaemblicin C compound at their binding interface. The phyllaemblicin and cinnamtannin class of phytochemicals can be potential inhibitors of both the spike and M^pro proteins of SARS-CoV-2; furthermore, its pharmacology and clinical optimization would lead towards novel COVID-19 small-molecule therapy.

Identifying best bioactive phytochemicals from different medicinal plants using molecular docking techniques demonstrates a potential pre-clinical compound discovery against SARS-CoV-2 viral infection.