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.     

In silico design of peptides with binding to the receptor binding domain (RBD) of the SARS-CoV-2 and their utility in bio-sensor development for SARS-CoV-2 detection

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people across the globe and created not only a health emergency but also a financial crisis. This virus attacks the angiotensin-converting enzyme 2 (ACE2) receptor situated on the surface of the host cell membrane. The spike protein of the virus binds to this receptor which is a critical step in infection. A molecule which can specifically stop this binding could be a potential therapeutic agent. In this study, we have tested 12 potential peptides which can bind to the receptor binding domain (RBD) of the spike protein of the virus and thus can potentially inhibit the binding of the latter on ACE2 receptors. These peptides are screened based on their binding with the RBD of the spike protein and aqueous stability, obtained using several atomistic molecular dynamic simulations. The potential of mean force calculation of peptides confirmed their binding to the RBD of the spike protein. Furthermore, two potential peptides were tested for use in a biosensing application for SARS-CoV-2 detection. Two types of biosensing platforms, a graphene sheet and a carbon nano tube (CNT) were tested. The peptides were modified in order to functionalize the graphene and CNT. Based on the interaction between the substrate, peptide and spike protein, the utility of the screened peptide for a given bio sensing platform is discussed and recommended.

The protocol for peptide design and testing for its usage as a sensor.     

Insight into the origin of SARS-CoV-2 through structural analysis of receptor recognition: a molecular simulation study

Bats and pangolins are considered to be potential hosts of the new coronavirus SARS-CoV-2, based on its genome similarity to coronaviruses of these species (Bat-CoV-RaTG13 and Pangolin-CoV). The receptor-binding domain (RBD), a functional component of the spike protein, is responsible for binding of SARS-CoV-2 by human ACE2 receptors and is also key to cross-species viral transmission. We performed molecular dynamics (MD) simulations using structures of hACE2 in complex with the RBD of SARS-CoV-2, SARS-CoV, Pangolin-CoV and Bat-CoV-RaTG13, respectively. By analyzing the hydrogen-bonding network at the RBD–hACE2 interface and estimating the binding free energies between RBD and hACE2, we found Pangolin-CoV bound hACE2 in a similar state as did SARS-CoV-2, and both of them bound hACE2 more strongly than did Bat-CoV-RaTG13 or SARS-CoV. We further identified two major adaptation mutations of SARS-CoV-2-RBD, which may have significant roles in regulating the recognition and binding between RBD and hACE2. Our results add to existing evidence that Pangolins have the potential to act as an intermediate host for SARS-CoV-2, and provide guidance for future design of antiviral drugs and vaccines.

The origin of SARS-CoV-2 through structural analysis of receptor recognition was investigated by molecular dynamics simulations.     

The SARS-CoV-2 B.1.618 variant slightly alters the spike RBD–ACE2 binding affinity and is an antibody escaping variant: a computational structural perspective

Continuing reports of new SARS-CoV-2 variants have caused worldwide concern and created a challenging situation for clinicians. The recently reported variant B.1.618, which possesses the E484K mutation specific to the receptor-binding domain (RBD), as well as two deletions of Tyr145 and His146 at the N-terminal binding domain (NTD) of the spike protein, must be studied in depth to devise new therapeutic options. Structural variants reported in the RBD and NTD may play essential roles in the increased pathogenicity of this SARS-CoV-2 new variant. We explored the binding differences and structural-dynamic features of the B.1.618 variant using structural and biomolecular simulation approaches. Our results revealed that the E484K mutation in the RBD slightly altered the binding affinity through affecting the hydrogen bonding network. We also observed that the flexibility of three important loops in the RBD required for binding was increased, which may improve the conformational optimization and consequently binding of the new variant. Furthermore, we found that deletions of Tyr145 and His146 at the NTD reduced the binding affinity of the monoclonal antibody (mAb) 4A8, and that the hydrogen bonding network was significantly affected consequently. This data show that the new B.1.618 variant is an antibody-escaping variant with slightly altered ACE2–RBD affinity. Moreover, we provide insights into the binding and structural-dynamics changes resulting from novel mutations in the RBD and NTD. Our results suggest the need for further in vitro and in vivo studies that will facilitate the development of possible therapies for new variants such as B.1.618.

This study explored the binding patterns of the wild type and B.1.618 variant using which revealed that the B.1.618 variant possess a stronger binding affinity for the host ACE2 and escape the neutralizing antibodies.     

Blocking key mutated hotspot residues in the RBD of the omicron variant (B.1.1.529) with medicinal compounds to disrupt the RBD-hACE2 complex using molecular screening and simulation approaches

A new variant of SARS-CoV-2 known as the omicron variant (B.1.1.529) reported in South Africa with 30 mutations in the whole spike protein, among which 15 mutations are in the receptor-binding domain, is continuously spreading exponentially around the world. The omicron variant is reported to be highly contagious with antibody-escaping activity. The emergence of antibody-escaping variants is alarming, and thus the quick discovery of small molecule inhibitors is needed. Hence, the current study uses computational drug screening and molecular dynamics simulation approaches (replicated) to identify novel drugs that can inhibit the binding of the receptor-binding domain (RBD) with hACE2. Screening of the North African, East African and North-East African medicinal compound databases by employing a multi-step screening approach revealed four compounds, namely (−)-pipoxide (C1), 2-(p-hydroxybenzyl) benzofuran-6-ol (C2), 1-(4-hydroxy-3-methoxyphenyl)-2-{4-[(E)-3-hydroxy-1-propenyl]-2-methoxyphenoxy}-1,3-propanediol (C3), and Rhein (C4), with excellent anti-viral properties against the RBD of the omicron variant. Investigation of the dynamics demonstrates stable behavior, good residue flexibility profiles, and structural compactness. Validation of the top hits using computational bioactivity analysis, binding free energy calculations and dissociation constant (K_D) analysis also indicated the anti-viral properties of these compounds. In conclusion, this study will help in the design and discovery of novel drug therapeutics, which may be used against the emerging omicron variant of SARS-CoV-2.

A new variant of SARS-CoV-2 known as the omicron variant (B.1.1.529) reported in South Africa with 30 mutations in the whole spike protein, among which 15 mutations are in the receptor-binding domain, is continuously spreading exponentially around the world.     

Binding of inhibitors to the monomeric and dimeric SARS-CoV-2 Mpro

SARS-CoV-2 rapidly infects millions of people worldwide since December 2019. There is still no effective treatment for the virus, resulting in the death of more than one million patients. Inhibiting the activity of SARS-CoV-2 main protease (Mpro), 3C-like protease (3CLP), is able to block the viral replication and proliferation. In this context, our study has revealed that in silico screening for inhibitors of SARS-CoV-2 Mpro can be reliably done using the monomeric structure of the Mpro instead of the dimeric one. Docking and fast pulling of ligand (FPL) simulations for both monomeric and dimeric forms correlate well with the corresponding experimental binding affinity data of 24 compounds. The obtained results were also confirmed via binding pose and noncovalent contact analyses. Our study results show that it is possible to speed up computer-aided drug design for SARS-CoV-2 Mpro by focusing on the monomeric form instead of the larger dimeric one.

Binding of inhibitors to the monomeric SARS-CoV-2 Mpro is similar to the dimeric one.     

Interaction analyses of SARS-CoV-2 spike protein based on fragment molecular orbital calculations

At the stage of SARS-CoV-2 infection in human cells, the spike protein consisting of three chains, A, B, and C, with a total of 3300 residues plays a key role, and thus its structural properties and the binding nature of receptor proteins to host human cells or neutralizing antibodies has attracted considerable interest. Here, we report on interaction analyses of the spike protein in both closed (PDB-ID: 6VXX) and open (6VYB) structures, based on large-scale fragment molecular orbital (FMO) calculations at the level of up to the fourth-order Møller–Plesset perturbation with singles, doubles, and quadruples (MP4(SDQ)). Inter-chain interaction energies were evaluated for both structures, and a mutual comparison indicated considerable losses of stabilization energies in the open structure, especially in the receptor binding domain (RBD) of chain-B. The role of charged residues in inter-chain interactions was illuminated as well. By two separate calculations for the RBD complexes with angiotensin-converting enzyme 2 (ACE2) (6M0J) and B38 Fab antibody (7BZ5), it was found that the binding with ACE2 or antibody partially compensated for this stabilization loss of RBD.

Visualized IFIE results seen from chain-B of spike protein.     

Molecular dynamics simulations and MM-GBSA reveal novel guanosine derivatives against SARS-CoV-2 RNA dependent RNA polymerase

According to the World Health Organization (WHO), SARS-CoV-2 is responsible for more than 5 M deaths and is reported in 223 countries infecting 250+ M people. Despite the current vaccination momentum, thousands of people die every day by COVID-19. Suggesting possible blockers of the viral RNA-dependent RNA polymerase is highly needed for potential effective therapeutics against SARS-CoV-2. This study utilizes combined molecular dynamics simulation and molecular docking to test novel guanosine derivatives against SARS-CoV-2 RdRp. Results reveal the binding potency of nineteen guanosine derivatives against SARS-CoV-2 solved structures. The bulky moieties (hydroxyl or fluorated phenyl moieties) added to the 2′ position of the ribose ring positively impacted the binding affinity to RdRp. The current in silico study represents a one-step-ahead for suggesting new possible blockers of SARS-CoV-2 RdRp that are yet to be verified in the wet lab. It offers new potential binders or blockers of RdRp that bind to the protein active site tighter than remdesivir. The latter was approved by the food and drug administration (FDA) for emergency use against COVID-19 last year.

According to the World Health Organization (WHO), SARS-CoV-2 is responsible for more than 5 M deaths and is reported in 223 countries infecting +250 M people.     

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.     

Ilimaquinone (marine sponge metabolite) as a novel inhibitor of SARS-CoV-2 key target proteins in comparison with suggested COVID-19 drugs: designing,docking and molecular dynamics simulation study

The outbreak of novel coronavirus, SARS-CoV-2, has infected more than 36 million people and caused approximately 1 million deaths around the globe as of 9 October 2020. The escalating outspread of the virus and rapid rise in the number of cases require the instantaneous development of effectual drugs and vaccines. Presently, there are no approved drugs or vaccine available to treat the infection. In such scenario, one of the propitious therapeutic approaches against viral infection is to explore enzyme inhibitors amidst natural compounds, utilizing computational approaches aiming to get products with negligible side effects. In the present study, the inhibitory prospects of ilimaquinone (marine sponge metabolite) were assessed in comparison with hydroxychloroquine, azithromycin, favipiravir, ivermectin and remdesivir at the active binding pockets of nine different vital SARS-CoV-2 target proteins (spike receptor binding domain, RNA-dependent RNA polymerase, Nsp10, Nsp13, Nsp14, Nsp15, Nsp16, main protease, and papain-like-protease), employing an in silico molecular interaction based approach. In addition, molecular dynamics (MD) simulations of the SARS-CoV-2 papain-like protease (PLpro)–ilimaquinone complex were also carried out to calculate various structural parameters including root mean square fluctuation (RMSF), root mean square deviation (RMSD), radius of gyration (R_g) and hydrogen bond interactions. PLpro is a promising drug target, due to its imperative role in viral replication and additional function of stripping ubiquitin and interferon-stimulated gene 15 (ISG15) from host-cell proteins. In light of the possible inhibition of all vital SARS-CoV-2 target proteins, our study has emphasized the importance to study in depth ilimaquinone actions in vivo.

Inhibitory potential of ilimaquinone (marine sponge metabolite) against nine essential SARS-CoV-2 target proteins, employing a molecular interaction and dynamics simulation approach.     

Newly designed analogues from SARS-CoV inhibitors mimicking the druggable properties against SARS-CoV-2 and its novel variants

The emerging variants of SARS coronavirus-2 (SARS-CoV-2) have been continuously spreading all over the world and have raised global health concerns. The B.1.1.7 (United Kingdom), P.1 (Brazil), B.1.351 (South Africa) and B.1.617 (India) variants, resulting from multiple mutations in the spike glycoprotein (SGp), are resistant to neutralizing antibodies and enable increased transmission. Hence, new drugs might be of great importance against the novel variants of SARS-CoV-2. The SGp and main protease (M^pro) of SARS-CoV-2 are important targets for designing and developing antiviral compounds for new drug discovery. In this study, we selected seventeen phytochemicals and later performed molecular docking to determine the binding interactions of the compounds with the two receptors and calculated several drug-likeliness properties for each compound. Luteolin, myricetin and quercetin demonstrated higher affinity for both the proteins and interacted efficiently. To obtain compounds with better properties, we designed three analogues from these compounds and showed their greater druggable properties compared to the parent compounds. Furthermore, we found that the analogues bind to the residues of both proteins, including the recently identified novel variants of SARS-CoV-2. The binding study was further verified by molecular dynamics (MD) simulation and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) approaches by assessing the stability of the complexes. MD simulations revealed that Arg457 of SGp and Met49 of M^pro are the most important residues that interacted with the designed inhibitors. Our analysis may provide some breakthroughs to develop new therapeutics to treat the proliferation of SARS-CoV-2 in vitro and in vivo.

Three designed inhibitors with potential inhibition efficacy against the emerging variants of SARS coronavirus-2 (SARS-CoV-2).     

Carbon nanotubes for rapid capturing of SARS-COV-2 virus: revealing a mechanistic aspect of binding based on computational studies

We investigate the binding interactions of synthesized multi-walled carbon nanotubes (MWCNTs) with SARS-CoV-2 virus. Two essential components of the SARS-CoV-2 structure i.e.6LU7 (main protease of SARS-CoV-2) and 6LZG (spike receptor-binding domain complexed with its receptor ACE2) were used for computational studies. MWCNTs of different morphologies (zigzag, armchair and chiral) were synthesized through a thermal chemical vapour deposition process as a function of pyrolysis temperature. A direct correlation between radius to volume ratio of the synthesized MWCNTs and the binding energies for all three (zigzag, armchair and chiral) conformations were observed in our computational studies. Our result suggests that MWCNTs interact with the active sites of the main protease along with the host angiotensin-converting enzyme2 (ACE2) receptors. Furthermore, it is also observed that MWCNTs have significant binding affinities towards SARS-CoV-2. However, the highest free binding energy of −87.09 kcal mol⁻¹ with 6LZG were shown by the armchair MWCNTs with SARS-CoV-2 through the simulated molecular dynamic trajectories, which could alter the SARS-CoV-2 structure with higher accuracy. The radial distribution function also confirms the density variation as a function of distance from a reference particle of MWCNTs for the study of interparticle interactions of the MWCNT and SARS-CoV-2. Due to these interesting attributes, such MWCNTs could find potential application in personal protective equipment (PPE) and diagnostic kits.

Investigation of the binding interactions of synthesized multi-walled carbon nanotubes (MWCNTs) with SARS-CoV-2 virus.     

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.     

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.     

The dolabellane diterpenes as potential inhibitors of the SARS-CoV-2 main protease: molecular insight of the inhibitory mechanism through computational studies

An investigation has been carried out on natural products from dolabellane derivatives to understand their potential in inhibiting the SARS-CoV-2 main protease (3CL^pro) using an in silico approach. Inhibition of the 3CL^pro enzyme is a promising target in stopping the replication of the SARS-CoV-2 virus through inhibition of the subsite binding pocket. The redocking process aims to determine the 3CL^pro active sites. The redocking requirement showed a good pose with an RMSD value of 1.39 Å. The combination of molecular docking and MD simulation shows the results of DD13 as a candidate which had a good binding affinity (kcal mol⁻¹) to inhibit the 3CL^pro enzyme activity. Prediction of binding free energy (kcal mol⁻¹) of DD13 using the Molecular Mechanics-Poisson Boltzmann/Generalized Born Surface Area (MM-PB/GBSA) approach shows the results ΔG_{bind(MM-GBSA)}: −52.33 ± 0.34 and ΔG_{bind(MM-PBSA)}: −43.52 ± 0.42. The key residues responsible for the inhibition mechanism are Hie41, Ser46, Met49, Asn142, Cys145, Hie163, Met165, and Gln189. Additionally, pharmacokinetic prediction recommended that DD13 had promising criteria as a drug candidate. The results demonstrated in this study provide theoretical information to obtain a potential inhibitor against the SARS-CoV-2 main protease.

An investigation on dolabellane derivatives to understand their potential in inhibiting the SARS-CoV-2 main protease (3CL^pro) using an in silico approach.     

In silico identification of SARS-CoV-2 spike (S) protein–ACE2 complex inhibitors from eight Tecoma species and cultivars analyzed by LC-MS

Coronavirus (CoV) is a positive RNA genome virus causing a global panic nowadays. Tecoma is a medicinally-valuable genus in the Bignoniaceae family, with some of its species exhibiting anti-HIV activity. This encouraged us to conduct an in silico exploration of some phytocompounds in Tecoma species cultivated in Egypt, namely Tecoma capensis and its four varieties i.e. yellow, harmony, pink and red, T. grandiflora Loisel., T. radicans L., and one hybrid i.e. Tecoma × smithii W. Watson. LC/MS-based metabolite profiling of the studied Tecoma plants resulted in the dereplication of 12 compounds (1–12) belonging to different phytochemical classes viz. alkaloids, iridoids, flavonoids and fatty acid esters. The in silico inhibitory action of these compounds against SARS-CoV-2 spike protein C-terminal domain in complex with human ACE2 was assessed via molecular docking. Succinic acid decyl-3-oxobut-2-yl ester (10), a fatty acid ester, possessed the best binding affinity (−6.77 kcal mol⁻¹), as compared to hesperidin (13) (−7.10 kcal mol⁻¹).

In silico exploration of 12 Tecoma phytocompounds that could serve as potential inhibitors of SARS-CoV entry to host cells.     

Investigating the structure–activity relationship of marine natural polyketides as promising SARS-CoV-2 main protease inhibitors

Since its first report in December 2019, the novel coronavirus virus, SARS-CoV-2, has caused an unprecedented global health crisis and economic loss imposing a tremendous burden on the worldwide finance, healthcare system, and even daily life. Even with the introduction of different preventive vaccines, there is still a dire need for effective antiviral therapeutics. Nature has been considered as the historical trove of drug discovery and development, particularly in cases of worldwide crises. Herein, a comprehensive in silico investigation of a highly focused chemical library of 34 pederin-structurally related marine compounds, belonging to four polyketides families, was initiated against the SARS-CoV-2 main protease, Mpro, being the key replicating element of the virus and main target in many drugs development programs. Two of the most potent SARS-CoV-2 Mpro co-crystallized inhibitors, O6K and N3, were added to the tested database as reference standards. Through molecular docking simulation, promising compounds including Pederin (1), Dihydro-onnamide A (11), Onnamide C (14), Pseudo-onnamide A (17), and Theopederin G (29) have been identified from different families based on their superior ligand–protein energies and relevant binding profiles with the key Mpro pocket residues. Thermodynamic behaviors of the identified compounds were investigated through 200 ns all-atom molecular dynamics simulation illustrating their significant stability and pocket accommodation. Furthermore, structural activity preferentiality was identified for the pederin-based marine compounds highlighting the importance of the terminal guanidine and cyclic hemiacetal linker, and the length of the sidechain. Our findings highlight the challenges of targeting SARS-CoV-2 Mpro as well as recommending further in vitro and in vivo studies regarding the examined marine products either alone or in combination paving the way for promising lead molecules.

Marine natural polyketides showed promising SARS-CoV-2 main protease inhibitory activities.     

A review on potential of natural products in the management of COVID-19

At the end of 2019, a life threatening viral infection (COVID-19) caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was reported. This virus has spread worldwide in a short duration and forced the world to face unprecedented life and economic loss. To date, there are no known specific drugs to combat this virus and the process for new drug development is lengthy. Most promising candidates, which emerged as potential leads, were abandoned in the later phases of clinical trials. Repurposing of already approved drugs for other therapeutic applications can be done only after extensive testing for safety and efficacy. With no definite therapeutics in the horizon, natural products are in extensive use arbitrarily as anti-viral agents and immune boosters. For ages it has been known that most natural products possess potent anti-viral activity and it is no different for SARS-CoV-2. It has been shown that natural products display inhibitory effects on MERS-CoV and SARS-CoV infections. In silico studies have shown that various natural products have strong binding affinity for and inhibitory action on the non-structural proteins of the virus, namely PL^PRO, M^PRO, and RdRp, and structural proteins such as spike (S) protein. Since the virus utilizes the transmembrane ACE2 receptor of the host cell, it also proves to be a valid target for drug development. In this review promising targets for drug development against SARS-CoV-2 and anti-viral activities of some of the known natural products are discussed.

In this review promising targets for drug development against SARS-CoV-2 and anti-viral activities of some of the known natural products (including plant secondary metabolites) are discussed.     

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.     

Novel huperzine A based NMDA antagonists: insights from molecular docking,ADME/T and molecular dynamics simulation studies

Huperzine A (HupA) is an alkaloidal natural product and drug isolated from Chinese herb Huperzia serrata, which is a potent selective anticholinesterase inhibitor. HupA has symptomatic, cognitive-enhancing and protective effect on neurons against amyloid beta-induced oxidative injury and antagonizing N-methyl-d-aspartate receptors by blocking the ion channels. The present study aimed to identify the docking, ADME/T and molecular dynamics simulation parameters of a library of 40 analogues which can correlate the binding affinity, conformational stability and selectivity of the ligands towards NMDA receptor through in silico approach. Glide molecular docking analysis was performed for the designed analogues to understand the binding mode and interactions. MD simulations were performed to explain the conformational stability and natural dynamics of the interaction in physiological environmental condition of protein–ligand complex affording a better understanding of chemical-scale interactions between HupA and its analogues with NMDA channel that could potentially benefit the development of new drugs for neurodegenerative diseases involving NMDA receptors.

The in silico study explores the structural behavior and binding affinities of 40 novel analogues of huperzine A. Novel NMDA receptor antagonists have been virtually identified by molecular docking, ADME/T and molecular dynamics simulation studies.