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.     

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.     

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.     

Mitoxantrone dihydrochloride,an FDA approved drug,binds with SARS-CoV-2 NSP1 C-terminal

One of the major virulence factors of SARS-CoV-2, NSP1, is a vital drug target due to its role in host immune evasion through multiple pathways. NSP1 protein is associated with inhibiting host mRNA translation by binding to the small subunit of ribosome through its C-terminal region. Previously, we have shown the structural dynamics of the NSP1 C-terminal region (NSP1-CTR) in different physiological environments. So, it would be very interesting to investigate the druggable compounds that could bind with NSP1-CTR. Here, in this article, we have performed different spectroscopic technique-based binding assays of an anticancer drug mitoxantrone dihydrochloride (MTX) against the NSP1-CTR. We have also performed molecular dynamics simulations of the docked complex with two different force fields up to one microsecond. Overall, our results have suggested good binding between NSP1-CTR and MTX and may have implications in developing therapeutic strategies targeting the NSP1 protein of SARS-CoV-2.

SARS-CoV-2 NSP1 is believed to be a potential drug target. Its C-terminal region which associates with ribosomal subunit has shown good binding with an anticancer drug, Mitoxantrone.     

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.     

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.     

Cold atmospheric pressure plasma for attenuation of SARS-CoV-2 spike protein binding to ACE2 protein and the RNA deactivation

Cold atmospheric pressure (CAP) plasma has a profound effect on protein–protein interactions. In this work, we have highlighted the deactivation of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike protein by CAP plasma treatment. Complete deactivation of spike protein binding to the human ACE2 protein was observed within an exposure time of 5 minutes which is correlated to the higher concentration of hydrogen peroxide formation due to the interaction with the reactive oxygen species present in the plasma. On the other hand, we have established that CAP plasma is also capable of degrading RNA of SARS-CoV-2 virus which is also linked to hydrogen peroxide concentration. The reactive oxygen species is produced in the plasma by using noble gases such as helium, in the absence of any other chemicals. Therefore, it is a green process with no chemical waste generated and highly advantageous from the environmental safety prospects. Results of this work could be useful in designing plasma-based disinfection systems over those based on environmentally hazardous chemical-based disinfection and biomedical applications.

Cold atmospheric pressure (CAP) plasma for the deactivation of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike protein binding to ACE2 protein.     

β-Blockers bearing hydroxyethylamine and hydroxyethylene as potential SARS-CoV-2 Mpro inhibitors: rational based design,in silico,in vitro,and SAR studies for lead optimization

The global COVID-19 pandemic became more threatening especially after the introduction of the second and third waves with the current large expectations for a fourth one as well. This urged scientists to rapidly develop a new effective therapy to combat SARS-CoV-2. Based on the structures of β-adrenergic blockers having the same hydroxyethylamine and hydroxyethylene moieties present in the HIV-1 protease inhibitors which were found previously to inhibit the replication of SARS-CoV, we suggested that they may decrease the SARS-CoV-2 entry into the host cell through their ability to decrease the activity of RAAS and ACE2 as well. Herein, molecular docking of twenty FDA-approved β-blockers was performed targeting SARS-CoV-2 Mpro. Results showed promising inhibitory activities especially for Carvedilol (CAR) and Nebivolol (NEB) members. Moreover, these two drugs together with Bisoprolol (BIS) as an example from the lower active ones were subjected to molecular dynamics simulations at 100 ns. Great stability across the whole 100 ns timeframe was observed for the top docked ligands, CAR and NEB, over BIS. Conformational analysis of the examined drugs and hydrogen bond investigation with the pocket''s crucial residues confirm the great affinity and confinement of CAR and NEB within the Mpro binding site. Moreover, the binding-free energy analysis and residue-wise contribution analysis highlight the nature of ligand–protein interaction and provide guidance for lead development and optimization. Furthermore, the examined three drugs were tested for their in vitro inhibitory activities towards SARS-CoV-2. It is worth mentioning that NEB achieved the most potential anti-SARS-CoV-2 activity with an IC₅₀ value of 0.030 μg ml⁻¹. Besides, CAR was found to have a promising inhibitory activity with an IC₅₀ of 0.350 μg ml⁻¹. Also, the IC₅₀ value of BIS was found to be as low as 15.917 μg ml⁻¹. Finally, the SARS-CoV-2 Mpro assay was performed to evaluate and confirm the inhibitory effects of the tested compounds (BIS, CAR, and NEB) towards the SARS-CoV-2 Mpro enzyme. The obtained results showed very promising SARS-CoV-2 Mpro inhibitory activities of BIS, CAR, and NEB (IC₅₀ = 118.50, 204.60, and 60.20 μg ml⁻¹, respectively) compared to lopinavir (IC₅₀ = 73.68 μg ml⁻¹) as a reference standard.

Hydroxyethylamine and hydroxyethylene moieties of β-blockers exert potential SARS-CoV-2 inhibitory effects: rational-based design and in silico, in vitro, and SAR Studies.     

Single point mutations can potentially enhance infectivity of SARS-CoV-2 revealed by in silico affinity maturation and SPR assay

The RBD (receptor binding domain) of the SARS-CoV-2 virus S (spike) protein mediates viral cell attachment and serves as a promising target for therapeutics development. Mutations on the S-RBD may alter its affinity to the cell receptor and affect the potency of vaccines and antibodies. Here we used an in silico approach to predict how mutations on RBD affect its binding affinity to hACE2 (human angiotensin-converting enzyme2). The effect of all single point mutations on the interface was predicted. SPR assay results show that 6 out of 9 selected mutations can strengthen binding affinity. Our prediction has reasonable agreement with the previous deep mutational scan results and recently reported mutants. Our work demonstrated the in silico method as a powerful tool to forecast more powerful virus mutants, which will significantly benefit the development of broadly neutralizing vaccine and antibody.

The RBD (receptor binding domain) of the SARS-CoV-2 virus S (spike) protein mediates viral cell attachment and serves as a promising target for therapeutics development.     

Inhibitory activity of quercetin,its metabolite,and standard antiviral drugs towards enzymes essential for SARS-CoV-2: the role of acid–base equilibria

The recently declared global pandemic of a new human coronavirus called SARS-CoV-2, which causes respiratory tract disease COVID-19, has reached worldwide resonance and global efforts are being made to look for possible cures. Sophisticated molecular docking software, as well as available protein sequence and structure information, offer the ability to test the inhibition of two important targets of SARS-CoV-2, furin (FUR) enzyme, and spike glycoprotein, or spike protein (SP), that are key to host cell adhesion and hijacking. The potential inhibitory effect and mechanism of action of acid–base forms of different antiviral drugs, dominant at physiological pH, chloroquine (CQ), hydroxychloroquine (HCQ), and cinanserin (CIN), which have been shown to be effective in the treatment of SARS-CoV-2 virus, is reported with the special emphasis on their relative abundances. On the other hand, the potential inhibitory effect of the dominant acid–base forms of quercetin (Q) and its oxidative metabolite 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H) benzofuranone (BZF), which are constituents of traditional food products believed to exhibit antiviral effects, was also examined. The undertaken study includes the determination of the major energy contributions to the binding energy as well as in-depth analysis of amino acid residues at the active pocket and possible interactions. The approach that we propose here may be an additional strategy for combating the deadly virus by preventing the first step of the virus replication cycle. Preliminary research has shown that the investigated compounds exert an inhibitory effect against the SARS-CoV-2 furin enzyme and spiked glycoprotein through different acid–base forms. These investigations may be helpful in creating potential therapeutic agents in the fight against the SARS-CoV-2 virus. On the other hand, the results we predicted in this computational study may be the basis for new experimental in vitro and in vivo studies.

Identification of potential inhibitory effect of acid–base species of quercetin and its metabolite as well as chloroquine, hydroxychloroquine, and cinanserin, at physiological pH, on proteins essential for SARS-CoV-2 virus survival.     

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.     

Dietary stigmastane-type saponins as promising dual-target directed inhibitors of SARS-CoV-2 proteases: a structure-based screening

Despite the development of COVID-19 vaccines, at present, there is still no approved antiviral drug against the pandemic. The SARS-CoV-2 3-chymotrypsin-like proteases (S-3CLpro) and papain-like protease (S-PLpro) are essential for the viral proliferation cycle, hence attractive drug targets. Plant-based dietary components that have been extensively reported for antiviral activities may serve as cheap sources of preventive nutraceuticals and/or antiviral drugs. A custom-made library of 176 phytochemicals from five West African antiviral culinary herbs was screened for potential dual-target-directed inhibitors of S-3CLpro and S-PLpro in silico. The docking analysis revealed fifteen steroidal saponins (FSS) from Vernonia amygdalina with the highest binding tendency for the active sites of S-3CLpro and S-PLpro. In an optimized docking analysis, the FSS were further docked against four equilibrated conformers of the S-3CLpro and S-PLpro. Three stigmastane-type steroidal saponins (vernonioside A2, vernonioside A4 and vernonioside D2) were revealed as the lead compounds. These compounds interacted with the catalytic residues of both S-3CLpro and S-PLpro, thereby exhibiting dual inhibitory potential against these SARS-CoV-2 cysteine proteases. The binding free energy calculations further corroborated the static and optimized docking analysis. The complexed proteases with these promising phytochemicals were stable during a full atomistic MD simulation while the phytochemicals exhibited favourable physicochemical and ADMET properties, hence, recommended as promising inhibitors of SARS-CoV-2 cysteine proteases.

Vernonia amygdalina derived phytochemicals as potential dual-target directed inhibitors of SARS-CoV-2 proteases from computational study perspective.     

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.     

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.     

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.     

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.     

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.     

Design,microwave-assisted synthesis,bioactivity and SAR of novel substituted 2-phenyl-2-cyclohexanedione enol ester derivatives

Based on the structure–activity relationship and active substructure combination, a novel class of substituted 2-phenyl-2-cyclohexanedione enol ester derivatives was designed for use as potential herbicide safeners. A microwave-assisted synthetic route was developed for the substituted 2-phenyl-2-cyclohexenone enol ester derivatives via coupling and acylation reactions. In the modified protocol, the reactions were performed under microwave irradiation, resulting in significant improvements in the yields and reaction times. All of the structures were characterized using IR, ¹H NMR, ¹³C NMR and HRMS spectroscopies. The bioassay results demonstrated that most of these compounds could alleviate clethodim injury to maize. Molecular docking modeling showed that the potential antagonism between compound 3(S24) and clethodim plays a key role in the metabolism of herbicides. This paper presents a new safener candidate for maize protection.

Based on the structure–activity relationship and active substructure combination, a novel class of substituted 2-phenyl-2-cyclohexanedione enol ester derivatives was designed for use as potential herbicide safeners.     

Synthesis,crystal structure and in silico studies of novel 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-ones

Herein, acetic acid mediated multicomponent synthesis of novel 2,4-dimethoxy-tetrahydropyrimido[4,5-b]quinolin-6(7H)-one (2,4-dimethoxy-THPQs) was reported. Single-crystal XRD analysis of four newly developed crystals of 2,4-dimethoxy-THPQs and their DFT study were also reported. The structure of all molecules was optimized using DFT B3LYP/6-31G(d) level and compared with the corresponding single-crystal XRD data. As a result, the theoretical and experimental geometrical parameters (bond lengths and bond angles) were found to be in good agreement. Frontier molecular orbital (FMO) and molecule electrostatic potential (MEP) analyses were used to investigate the physicochemical properties and relative reactivity of 2,4-dimethoxy-THPQs. The formation of strong C–H⋯O and N–H⋯O interaction was investigated by Hirshfeld analysis. Furthermore, electronic charge density concentration in 2,4-dimethoxy-THPQs was analysed by the Mulliken atomic charges which helps to predict the ability of 2,4-dimethoxy-THPQs to bind in the receptor. The molecular docking of the crystal structure of 2,4-dimethoxy-THPQs in the main protease (M^pro) of SARS-CoV-2 suggested that all four 2,4-dimethoxy-THPQs efficiently docked in M^pro. Furthermore, 2,4-dimethoxy-THPQs with a 3-chloro substitution in the phenyl ring have the highest binding affinity because of the additional formation of halogen bonds and highest dipole moment.

Single-crystal XRD analysis of 2,4-dimethoxy THPQs and their relative reactivity with properties were investigated using DFT calculation. Molecular docking studies show they effectively docked with main protease of SARS-CoV-2.