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Imidazole-based compounds form a prominent class of heterocyclic compounds, displaying diverse applications, especially with regards to its biological and pharmacological activities. Molecular docking, simulations, and drug-likeness prediction were performed on 45 imidazole-based alkaloids from two species of marine sponges (Leucetta and Clathrina). The study seeks to identify possible inhibitors of the SARS-CoV-2 Main Protease in an effort to battle the prevailing pandemic which has been caused by the widespread infections of the SAR-CoV-2 virus in its varied mutated forms. Computational analysis with MOE 2015.10 program reveals that, among the imidazole-based alkaloids, Naamidines have a high affinity for the target protein (PDB ID:6W63), even interacting with the catalytic dyad, as compared to its non-covalent inhibitor X77. Among all the top-scoring ligands, Naamidine H produced the highest binding score of −8.87078 kcal/mol. MD simulation studies with NAMD confirms the stability of the interactions of Naamidines with the target protein. MM-GBSA calculations were performed on the top binding ligands which further confirms the binding affinity of the top-scoring ligands. Computational and pharmacological investigations in this study proposes Naamidines, as effective inhibitors of Mpro. Naamidine I, Naamidine E, and Pyronaamidine could be potential anti-viral candidates against SAR-CoV-2. [ABSTRACT FROM AUTHOR]

Phytochemical investigation of the whole plants of Vernonia gratiosa Hance. led in the isolation and identification of two new stigmastane-type steroidal glucosides (1–2), namely vernogratiosides A (1), and B (2). Their chemical structures were fully elucidated based on 1 D/2D NMR spectroscopic, HR-ESI-MS data analyses, and by producing derivatives by chemical reactions. The binding potential of the isolated compounds to replicase protein − main protease of SARS-CoV-2 were examined using the molecular docking simulations. Our results show that the isolated steroidal glucosides (1–2) bind to the substrate‐binding site of SARS-CoV-2 main protease with binding affinities of −7.2 and −7.6 kcal/mol, respectively, as well as binding abilities equivalent to N3 inhibitor that has already been reported (–7.5 kcal/mol). [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 main protease (Mpro) is essential for the life cycle of the COVID-19 virus. It cleaves the two polyproteins at 11 positions to generate mature proteins for virion formation. The cleavage site on these polyproteins is known to be Leu-Gln↓(Ser/Ala/Gly). A range of hexapeptides that follow the known sequence for recognition and cleavage was constructed using RDKit libraries and complexed with the crystal structure of Mpro (PDB ID 6XHM) through extensive molecular docking calculations. A subset of 131 of these complexes underwent 20 ns molecular dynamics simulations. The analyses of the trajectories from molecular dynamics included principal component analysis (PCA), and a method to compare PCA plots from separate trajectories was developed in terms of encoding PCA progression during the simulations. The hexapeptides formed stable complexes as expected, with reproducible molecular docking of the substrates given the extensiveness of the procedure. Only Lys-Leu-Gln*** (KLQ***) sequence complexes were studied for molecular dynamics. In this subset of complexes, the PCA analysis identified four classifications of protein motions across these sequences. KLQ*** complexes illustrated the effect of changes in substrate on the active site, with implications for understanding the substrate recognition of Mpro and informing the development of small molecule inhibitors. [ABSTRACT FROM AUTHOR]

Aim: To evaluate using bioinformatics tools the interactions between plant protease inhibitors (PIs) and SARS-CoV-2 Mpro. Materials & methods: This was an in silico study based on molecular docking, molecular dynamics simulations and quantum biochemistry calculations. Results: The plant PIs pineapple cystatin and sesame cystatin interacted allosterically with Mpro, leading to significant structural alterations. These conformational changes lead to a reduction of the area and volume of the Mpro proteolytic site, likely affecting the protease activity and, consequently, reducing viral replication. Conclusion: This work highlights the therapeutic potential of plant PIs as candidates for future in vivo investigations into new therapeutics for COVID-19. [ABSTRACT FROM AUTHOR]

The current outbreak of coronavirus disease 2019 (COVID-19) has prompted the necessity of efficient treatment strategies. The COVID-19 pandemic was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Main protease (Mpro), also called 3-chymotrypsin-like protease (3CL protease), plays an essential role in cleaving virus polyproteins for the functional replication complex. Therefore, Mpro is a promising drug target for COVID-19 therapy. Through molecular modelling, docking and a protease activity assay, we found four novel inhibitors targeting Mpro with the half maximal inhibitory concentration (IC50) and their binding affinities shown by the dissociation constants (KDs). Our new inhibitors CB-21, CB-25, CP-1 and LC24-20 have IC50s at 14.88 µM (95% Confidence Interval (95% CI): 10.35 µM to 20.48 µM), 22.74 µM (95% CI: 13.01 µM to 38.16 µM), 18.54µM (95% CI: 6.54 µM to 36.30 µM) and 32.87µM (95% CI: 18.37 µM to 54.80 µM)), respectively. The evaluation of interactions suggested that each inhibitor has a hydrogen bond or hydrophobic interactions with important residues, including the most essential catalytic residues: His41 and Cys145. All the four inhibitors have a much higher 50% lethal dose (LD50) compared with the well-known Mpro inhibitor GC376, demonstrating its low toxicity. These four inhibitors can be potential drug candidates for further in vitro and in vivo studies against COVID-19. [ABSTRACT FROM AUTHOR]

To control the COVID-19 pandemic, antivirals that specifically target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently required. The 3-chymotrypsin-like protease (3CLpro) is a promising drug target since it functions as a catalytic dyad in hydrolyzing polyprotein during the viral life cycle. Bioactive peptides, especially food-derived peptides, have a variety of functional activities, including antiviral activity, and also have a potential therapeutic effect against COVID-19. In this study, the hemp seed trypsinized peptidome was subjected to computer-aided screening against the 3CLpro of SARS-CoV-2. Using predictive trypsinized products of the five major proteins in hemp seed (i.e., edestin 1, edestin 2, edestin 3, albumin, and vicilin), the putative hydrolyzed peptidome was established and used as the input dataset. To select the Cannabis sativa antiviral peptides (csAVPs), a predictive bioinformatic analysis was performed by three webserver screening programs: iAMPpred, AVPpred, and Meta-iAVP. The amino acid composition profile comparison was performed by COPid to screen for the non-toxic and non-allergenic candidates, ToxinPred and AllerTOP and AllergenFP, respectively. GalaxyPepDock and HPEPDOCK were employed to perform the molecular docking of all selected csAVPs to the 3CLpro of SARS-CoV-2. Only the top docking-scored candidate (csAVP4) was further analyzed by molecular dynamics simulation for 150 nanoseconds. Molecular docking and molecular dynamics revealed the potential ability and stability of csAVP4 to inhibit the 3CLpro catalytic domain with hydrogen bond formation in domain 2 with short bonding distances. In addition, these top ten candidate bioactive peptides contained hydrophilic amino acid residues and exhibited a positive net charge. We hope that our results may guide the future development of alternative therapeutics against COVID-19. [ABSTRACT FROM AUTHOR]

A global crisis of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has impacted millions of people’s lives throughout the world. In parallel to vaccine development, identifying potential antiviral agents against SARS-CoV-2 has become an urgent need to combat COVID-19. One of the most attractive drug targets for discovering anti-SARS-CoV-2 agents is the main protease (Mpro), which plays a pivotal role in the viral life cycle. This study aimed to elucidate a series of twenty-one 12-dithiocarbamate-14-deoxyandrographolide analogues as SARS-CoV-2 Mpro inhibitors using in vitro and in silico studies. These compounds were initially screened for the inhibitory activity toward SARS-CoV-2 Mpro by in vitro enzyme-based assay. We found that compounds 3k, 3l, 3m and 3t showed promising inhibitory activity against SARS-CoV-2 Mpro with >50% inhibition at 10 μM. Afterward, the binding mode of each compound in the active site of SARS-CoV-2 Mpro was explored by molecular docking. The optimum docked complexes were then chosen and subjected to molecular dynamic (MD) simulations. The MD results suggested that all studied complexes were stable along the simulation time, and most of the compounds could fit well with the SARS-CoV-2 Mpro active site, particularly at S1, S2 and S4 subsites. The per-residue decomposition free energy calculations indicated that the hot-spot residues essential for ligand binding were T25, H41, C44, S46, M49, C145, H163, M165, E166, L167, D187, R188, Q189 and T190. Therefore, the obtained information from the combined experimental and computational techniques could lead to further optimization of more specific and potent andrographolide analogues toward SARS-CoV-2 Mpro.

The recent global health emergency caused by the coronavirus disease 2019 (COVID-19) pandemic has taken a heavy toll, both in terms of lives and economies. Vaccines against the disease have been developed, but the efficiency of vaccination campaigns worldwide has been variable due to challenges regarding production, logistics, distribution and vaccine hesitancy. Furthermore, vaccines are less effective against new variants of the SARS-CoV-2 virus and vaccination-induced immunity fades over time. These challenges and the vaccines' ineffectiveness for the infected population necessitate improved treatment options, including the inhibition of the SARS-CoV-2 main protease (Mpro). Drug repurposing to achieve inhibition could provide an immediate solution for disease management. Here, we used structure-based virtual screening (SBVS) to identify natural products (from NP-lib) and FDA-approved drugs (from e-Drug3D-lib and Drugs-lib) which bind to the Mpro active site with high-affinity and therefore could be designated as potential inhibitors. We prioritized nine candidate inhibitors (e-Drug3D-lib: Ciclesonide, Losartan and Telmisartan; Drugs-lib: Flezelastine, Hesperidin and Niceverine; NP-lib: three natural products) and predicted their half maximum inhibitory concentration using DeepPurpose, a deep learning tool for drug–target interactions. Finally, we experimentally validated Losartan and two of the natural products as in vitro Mpro inhibitors, using a bioluminescence resonance energy transfer (BRET)-based Mpro sensor. Our study suggests that existing drugs and natural products could be explored for the treatment of COVID-19. [ABSTRACT FROM AUTHOR]

Monosaccharide derivatives are of importance in the field of carbohydrate chemistry because of their effectiveness in the synthesis of biologically active products. As a consequence, the chemistry and biochemistry of carbohydrate derivatives are an essential part of biochemical and medicinal research. In this work, we have explored the speciation of acylated methyl 6-O-myristoyl-α-D-glucopyranoside derivatives (2-9) to find the pharmacodynamics, toxicity profiles, and biological activities by using ADMET studies. PASS prediction also indicated that these acylated derivatives (2-9) are more potent as anticarcinogenic agents than as antioxidant agents. Quantum mechanical study employing density functional theory with B3LYP/6-31G(d,p) for investigating the enthalpies (ΔH), Gibbs free energies (ΔG), entropies (ΔS), and molecular orbital (HOMO-LUMO gap, hardness, softness, chemical potential, and electrophilicity index), dipole moment and natural bond orbital revealed that these derivatives are thermodynamically stable. The molecular docking study revealed that ivermectin has the highest binding affinity (-8.1 kcal mol-1) and, among the tested compounds, 2 and 3 (-5.7 kcal mol-1) showed the highest binding affinity, followed by 4 and 5 (-5.5 kcal mol-1). These results of acylated derivatives (2-9) could be useful for the development of drugs. [ABSTRACT FROM AUTHOR]

The Coronavirus Disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the loss of life and has affected the life quality, economy, and lifestyle. The SARS-CoV-2 main protease (Mpro), which hydrolyzes the polyprotein, is an interesting antiviral target to inhibit the spreading mechanism of COVID-19. Through predictive digestion, the peptidomes of the four major proteins in rice bran, albumin, glutelin, globulin, and prolamin, with three protease enzymes (pepsin, trypsin, and chymotrypsin), the putative hydrolyzed peptidome was established and used as the input dataset. Then, the prediction of the antiviral peptides (AVPs) was performed by online bioinformatics tools, i.e., AVPpred, Meta-iAVP, AMPfun, and ENNAVIA programs. The amino acid composition and cytotoxicity of candidate AVPs were analyzed by COPid and ToxinPred, respectively. The ten top-ranked antiviral peptides were selected and docked to the SARS-CoV-2 main protease using GalaxyPepDock. Only the top docking scored candidate (AVP4) was further analyzed by molecular dynamics simulation for one nanosecond. According to the bioinformatic analysis results, the candidate SARS-CoV-2 main protease inhibitory peptides were 7–33 amino acid residues and formed hydrogen bonds at Thr22–24, Glu154, and Thr178 in domain 2 with short bonding distances. In addition, these top-ten candidate bioactive peptides contain hydrophilic amino acid residues and have a positive net charge. We hope that this study will provide a potential starting point for peptide-based therapeutic agents against COVID-19. [ABSTRACT FROM AUTHOR]

• Identified the inhibitory ability of 35 flavonoids on SARS-CoV-2 Mpro. • A reliable and predictive 3D-QSAR model was developed. • A series of compounds with good activity have been synthesized. The damage to public health posed by the COVID-19 epidemic remains non-negligible, and research into highly effective antiviral drugs is key to addressing the epidemic. The main protease (Mpro) is critical for SARS-CoV-2 replication and acts as an effective target for drug development. To date, many flavonoid compounds have been reported to exhibit inhibition of Mpro, and flavonoid structures are informative for the development of new inhibitors. In the present study, we first evaluated the ability of 35 flavonoid compounds to bind Mpro and found that the hydrophobic interaction generated between the benzene ring and the residues may be the main source of binding force. The in vitro inhibitory activity of these compounds was tested by the FRET method, and most of them showed significant inhibition of Mpro. Preliminary analysis revealed that the presence of the glycosidic group was detrimental to the activity of the compounds, in addition the position of the hydroxyl substituent had an effect on the activity of the compounds. Reliable and predictive CoMFA (q2 = 0.541, r2 = 0.998, SEE = 0.039) and CoMISA (q2 = 0.554, r2 = 0.999, SEE = 0.034) models were developed, and the compounds were analyzed by 3D-QSAR with modeled steric, electrostatic, hydrogen bond donor, and hydrophobic fields. A series of compounds were synthesized and characterized, which showed similar experimental and predicted activities, with the activity of 15d (IC 50 = 0.74 ± 0.04 uM) exceeding that of the template molecule 15 (0.98 ± 0.13 uM). Subsequently, molecular docking revealed the binding mode of 15d to Mpro and verified the predictions of steric, hydrogen bond donor, and hydrophobic field. In conclusion, these findings provide ideas for subsequent structural studies of flavonoids that could be used in the development of flavonoid-type SARS-CoV-2 Mpro inhibitors. [Display omitted] [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 main protease (Mpro) is essential for the life cycle of the COVID-19 virus. It cleaves the two polyproteins at 11 positions to generate mature proteins for virion formation. The cleavage site on these polyproteins is known to be Leu-Gln↓(Ser/Ala/Gly). A range of hexapeptides that follow the known sequence for recognition and cleavage was constructed using RDKit libraries and complexed with the crystal structure of Mpro (PDB ID 6XHM) through extensive molecular docking calculations. A subset of 131 of these complexes underwent 20 ns molecular dynamics simulations. The analyses of the trajectories from molecular dynamics included principal component analysis (PCA), and a method to compare PCA plots from separate trajectories was developed in terms of encoding PCA progression during the simulations. The hexapeptides formed stable complexes as expected, with reproducible molecular docking of the substrates given the extensiveness of the procedure. Only Lys-Leu-Gln*** (KLQ***) sequence complexes were studied for molecular dynamics. In this subset of complexes, the PCA analysis identified four classifications of protein motions across these sequences. KLQ*** complexes illustrated the effect of changes in substrate on the active site, with implications for understanding the substrate recognition of Mpro and informing the development of small molecule inhibitors.

One of the promising therapeutic strategies for corona virus 2019 (COVID-19) is tolook for enzyme inhibitors. COVID-19 virus main protease (Mpro) plays a vital role in mediating viral transcription and replication, introducing it as an attractive antiviral agent target. LC–ESI–HDMS based metabolic profiling of Citrus nobilis Lour. ×Citrus deliciosa Ten. (Rutaceae) annotated 21 compounds belonging to diverse classes. Molecular docking studies were carried out to ascertain the inhibitory action of studied dereplicated compounds through the interactions within the active site of SARS-CoV-2 (Mpro). Among which, quercetin-7-O-glucoside-3-O-rutinoside (21) possessed the best binding affinity (–9.47 kcal/mol), followed by luteoline-7-rutinoside (18), quercetin-3-O-rutinoside (19) and apigenin-8-C-glucoside (15) showed less binding affinities ranging at −8.27, −7.97 and −6.94 kcal/mol respectively. [ABSTRACT FROM AUTHOR]

Coronaviruses caused an outbreak pandemic disease characterized by a severe acute respiratory distress syndrome leading to the infection of more than 200 million patients and the death of more than 4 million individuals. The primary treatment is either supportive or symptomatic. Natural products have an important role in the development of various drugs. Thus, screening of natural compounds with reported antiviral activities can lead to the discovery of potential inhibitory entities against coronaviruses. In the current study, an in-silico molecular docking experiment was conducted on the effects of some of these natural antiviral phytoconstituents, (e.g., procyanidin B2, theaflavin, quercetin, ellagic acid, caffeoylquinic acid derivatives, berginin, eudesm-1ß, 6a, 11-triol and arbutin), on the crystal structure of SARS-CoV-2 main protease (PDB ID: 6w63) using AutoDock-Vina software. Many of the docked compounds revealed good binding affinity, with procyanidin B2 (-8.6 Kcal/mol) and theaflavin (-8.5 Kcal/mol) showing a better or similar binding score as the ligand (-8.5 Kcal/mol). Molecular dynamics simulations were carried out at 100 ns and revealed that procyanidin B2 forms a more stable complex with SARS-CoV-2 main protease than theaflavin. Procyanidin B2, theaflavin, and 4,5-dicaffeoylquinic acid were evaluated for toxicity by ProTox-II webserver and were non-toxic according to the predicted LD50 values and safe on different organs and pathways. Additionally, these phytoconstituents showed good ADME properties and acceptable lipophilicity, as evaluated using WLOGP. Amongst the tested compounds, procyanidin B2 showed the highest lipophilic value. It is worth mentioning that these natural inhibitiors of SARS-CoV-2 main protease are components of green and black tea that can be used as a supporting supplement for COVID patients or as potential nuclei for further drug design and development campaigns. [ABSTRACT FROM AUTHOR]

Since the time of its appearance until present, COVID-19 has spread worldwide, with over 71 million confirmed cases and over 1.6 million deaths reported by the World Health Organization (WHO). In addition to the fact that cases of COVID-19 are increasing worldwide, the Delta and Omicron variants have also made the situation more challenging. Herein, we report the evaluation of several thiazole/thiadiazole/benzothiazole based thiazolidinone derivatives which were chosen from 112 designed derivatives by docking as potential molecules to inhibit the main protease of SARS-CoV-2. The contained experimental data revealed that among the fifteen compounds chosen, five compounds (k3, c1, n2, A2, A1) showed inhibitory activity with IC50 within the range of 0.01–34.4 μΜ. By assessing the cellular effects of these molecules, we observed that they also had the capacity to affect the cellular viability of human normal MRC-5 cells, albeit with a degree of variation. More specifically, k3 which is the most promising compound with the higher inhibitory capacity to SARS-CoV-2 protease (0.01 μΜ) affects in vitro cellular viability only by 57% at the concentration of 0.01 μM after 48 h in culture. Overall, these data provide evidence on the potential antiviral activity of these molecules to inhibit the main protease of SARS-CoV-2, a fact that sheds light on the chemical structure of the thiazole/thiadiazole/benzothiazole based thiazolidin-4-one derivatives as potential candidates for COVID-19 therapeutics. [ABSTRACT FROM AUTHOR]

In the search for new anti-HIV-1 agents, two forms of phenylamino-phenoxy-quinoline derivatives have been synthesized, namely, 2-phenylamino-4-phenoxy-quinoline and 6-phenylamino-4-phenoxy-quinoline. In this study, the binding interactions of phenylamino-phenoxy-quinoline derivatives and six commercially available drugs (hydroxychloroquine, ritonavir, remdesivir, S-217622, N3, and PF-07321332) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) were investigated using molecular docking and the ONIOM method. The molecular docking showed the hydrogen bonding and hydrophobic interactions of all the compounds in the pocket of SARS-CoV-2 main protease (Mpro), which plays an important role for the division and proliferation of the virus into the cell. The binding free energy values between the ligands and Mpro ranged from −7.06 to −10.61 kcal/mol. The molecular docking and ONIOM results suggested that 4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline and 4-(4′-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline have low binding energy values and appropriate molecular properties; moreover, both compounds could bind to Mpro via hydrogen bonding and Pi-Pi stacking interactions with amino acid residues, namely, HIS41, GLU166, and GLN192. These amino acids are related to the proteolytic cleavage process of the catalytic triad mechanisms. Therefore, this study provides important information for further studies on synthetic quinoline derivatives as antiviral candidates in the treatment of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Due to the length of time required to develop specific antiviral agents, the World Health Organization adopted the strategy of repurposing existing medications to treat Coronavirus disease 2019 infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease is possible biological target for potential antiviral drugs. We selected various compounds from PubChem database based on the structure of main protease inhibitors in Protein Data Bank database. Ten compounds showed nontumorigenic and nonmutagenic potential and met Egan's and Lipinski's rules. Molecular docking analysis was performed using AutoDock Vina software. Based on number and type of key binding interactions, as well as docking scores, we selected compounds 6, 8, and 17 that demonstrated the highest binding affinity for the target protein. Molecular dynamics simulations were then carried out on the protein-top docked ligand complexes which were subjected to molecular mechanics/generalized Born and surface area calculations. The molecular dynamics simulation results indicated that protein-top docked ligand complexes showed good conformational stability. Among analyzed molecules, compound 17 emerged as the best in silico hit based on the docking score, MM/GBSA binding energy and MD results. [ABSTRACT FROM AUTHOR]

Natural compounds obtained from various sources have been used in the treatment of many diseases for many years and are very important compounds for drug development studies. They can also be an option to treat COVID-19, which is affecting the whole world and not curable with medication, yet. In this study, two 2-arylbenzofuran derivatives from Sesbania cannabina which are newly entered the literature were investigated computationally with the assistance of computational techniques including DFT calculations, molecular docking calculation and molecular dynamics simulations. The study consists of four parts, in the first part of the study DFT calculations were performed on the 2-arylbenzofurans, and geometry optimizations, vibrational analyses, molecular electrostatic potential (MEP) map calculations, frontier molecular orbital (FMO) calculations and Mulliken charge analyses were carried out. In the second part, molecular docking calculations were performed to investigate the interactions between the molecules and two potential target, SARS-CoV-2 main protease (SARS-CoV-2 Mpro) and SARS-CoV-2 spike receptor binding domain – human angiotensin converting enzyme 2 complex (SARS-CoV-2 SRBD – hACE2). In the third part, MD simulations were performed on the top-scoring ligand – receptor complexes to investigate the stability of the complex and the interactions between ligands and receptors in more detail. Finally, drug-likeness analyses and ADME (adsorption, desorption, metabolism, excretion) predictions were performed on the investigated compounds. Results showed that investigated natural compounds effectively interacted with the target receptors and gave comparable results to the reference drug molecules. [ABSTRACT FROM AUTHOR]

This work presented the microwave assisted synthesis of six new 2́-hydroxychalcones and their characterization based on FTIR, UV–Vis, 1H NMR, and mass spectral analysis. Quantum chemical studies confirmed the structures of prepared chalcones. Antioxidant, in vitro antimicrobial and in silico antiviral studies have been performed to evaluate their biological performance. Results of molecular docking of prepared 2́-hydroxychalcones against SARS-CoV-2 (7BQY) main protease disclosed their inhibition which is comparable to standard, remdesivir and better than hydroxychloroquine (HCQ). ADMET prediction revealed them to be non-carcinogenic and relatively safe.

The current outbreak of coronavirus disease 2019 (COVID-19) has prompted the necessity of efficient treatment strategies. The COVID-19 pandemic was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Main protease (Mpro), also called 3-chymotrypsin-like protease (3CL protease), plays an essential role in cleaving virus polyproteins for the functional replication complex. Therefore, Mpro is a promising drug target for COVID-19 therapy. Through molecular modelling, docking and a protease activity assay, we found four novel inhibitors targeting Mpro with the half maximal inhibitory concentration (IC50) and their binding affinities shown by the dissociation constants (KDs). Our new inhibitors CB-21, CB-25, CP-1 and LC24-20 have IC50s at 14.88 µM (95% Confidence Interval (95% CI): 10.35 µM to 20.48 µM), 22.74 µM (95% CI: 13.01 µM to 38.16 µM), 18.54µM (95% CI: 6.54 µM to 36.30 µM) and 32.87µM (95% CI: 18.37 µM to 54.80 µM)), respectively. The evaluation of interactions suggested that each inhibitor has a hydrogen bond or hydrophobic interactions with important residues, including the most essential catalytic residues: His41 and Cys145. All the four inhibitors have a much higher 50% lethal dose (LD50) compared with the well-known Mpro inhibitor GC376, demonstrating its low toxicity. These four inhibitors can be potential drug candidates for further in vitro and in vivo studies against COVID-19.

In this study, the interactions between the inhibitors and the main protease (Mpro) of SARS-CoV-2 were studied, to understand how the inhibitors influence the dynamics of Mpro of SARS-CoV-2. Firstly, molecular docking was applied to obtain the binding complex of the inhibitors and the main protease, and the binding affinities. The classical molecular dynamics simulations show that, all the tested inhibitors cannot inhibit the dynamics of Mpro’s active pocket. The replica-exchange molecular dynamics simulations show that, the inhibitors influence the shape of the active pocket of Mpro. With the formation of hydrogen bonds between the inhibitors and different sites of the active pocket, the inhibitors affect the length and width of the pocket. The study indicates that the drug design of Mpro should fully consider the importance of the hydrogen network between the potential inhibitors and the active pocket. In this study, the interactions between the inhibitors and the main protease (Mpro) of SARS-CoV-2 were studied, to understand how the inhibitors influence the dynamics of Mpro of SARS-CoV-2. Firstly, molecular docking was applied to obtain the binding complex of the inhibitors and the main protease, and the binding affinities. The classical molecular dynamics simulations show that, all the tested inhibitors cannot inhibit the dynamics of Mpro’s active pocket. The replica-exchange molecular dynamics simulations show that, the inhibitors influence the shape of the active pocket of Mpro. With the formation of hydrogen bonds between the inhibitors and different sites of the active pocket, the inhibitors affect the length and width of the pocket. The study indicates that the drug design of Mpro should fully consider the importance of the hydrogen network between the potential inhibitors and the active pocket. [ABSTRACT FROM AUTHOR]

To control the COVID-19 pandemic, antivirals that specifically target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently required. The 3-chymotrypsin-like protease (3CLpro) is a promising drug target since it functions as a catalytic dyad in hydrolyzing polyprotein during the viral life cycle. Bioactive peptides, especially food-derived peptides, have a variety of functional activities, including antiviral activity, and also have a potential therapeutic effect against COVID-19. In this study, the hemp seed trypsinized peptidome was subjected to computer-aided screening against the 3CLpro of SARS-CoV-2. Using predictive trypsinized products of the five major proteins in hemp seed (i.e., edestin 1, edestin 2, edestin 3, albumin, and vicilin), the putative hydrolyzed peptidome was established and used as the input dataset. To select the Cannabis sativa antiviral peptides (csAVPs), a predictive bioinformatic analysis was performed by three webserver screening programs: iAMPpred, AVPpred, and Meta-iAVP. The amino acid composition profile comparison was performed by COPid to screen for the non-toxic and non-allergenic candidates, ToxinPred and AllerTOP and AllergenFP, respectively. GalaxyPepDock and HPEPDOCK were employed to perform the molecular docking of all selected csAVPs to the 3CLpro of SARS-CoV-2. Only the top docking-scored candidate (csAVP4) was further analyzed by molecular dynamics simulation for 150 nanoseconds. Molecular docking and molecular dynamics revealed the potential ability and stability of csAVP4 to inhibit the 3CLpro catalytic domain with hydrogen bond formation in domain 2 with short bonding distances. In addition, these top ten candidate bioactive peptides contained hydrophilic amino acid residues and exhibited a positive net charge. We hope that our results may guide the future development of alternative therapeutics against COVID-19.

The recent global health emergency caused by the coronavirus disease 2019 (COVID-19) pandemic has taken a heavy toll, both in terms of lives and economies. Vaccines against the disease have been developed, but the efficiency of vaccination campaigns worldwide has been variable due to challenges regarding production, logistics, distribution and vaccine hesitancy. Furthermore, vaccines are less effective against new variants of the SARS-CoV-2 virus and vaccination-induced immunity fades over time. These challenges and the vaccines’ ineffectiveness for the infected population necessitate improved treatment options, including the inhibition of the SARS-CoV-2 main protease (Mpro). Drug repurposing to achieve inhibition could provide an immediate solution for disease management. Here, we used structure-based virtual screening (SBVS) to identify natural products (from NP-lib) and FDA-approved drugs (from e-Drug3D-lib and Drugs-lib) which bind to the Mpro active site with high-affinity and therefore could be designated as potential inhibitors. We prioritized nine candidate inhibitors (e-Drug3D-lib: Ciclesonide, Losartan and Telmisartan; Drugs-lib: Flezelastine, Hesperidin and Niceverine; NP-lib: three natural products) and predicted their half maximum inhibitory concentration using DeepPurpose, a deep learning tool for drug–target interactions. Finally, we experimentally validated Losartan and two of the natural products as in vitro Mpro inhibitors, using a bioluminescence resonance energy transfer (BRET)-based Mpro sensor. Our study suggests that existing drugs and natural products could be explored for the treatment of COVID-19.

The Coronavirus Disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the loss of life and has affected the life quality, economy, and lifestyle. The SARS-CoV-2 main protease (Mpro), which hydrolyzes the polyprotein, is an interesting antiviral target to inhibit the spreading mechanism of COVID-19. Through predictive digestion, the peptidomes of the four major proteins in rice bran, albumin, glutelin, globulin, and prolamin, with three protease enzymes (pepsin, trypsin, and chymotrypsin), the putative hydrolyzed peptidome was established and used as the input dataset. Then, the prediction of the antiviral peptides (AVPs) was performed by online bioinformatics tools, i.e., AVPpred, Meta-iAVP, AMPfun, and ENNAVIA programs. The amino acid composition and cytotoxicity of candidate AVPs were analyzed by COPid and ToxinPred, respectively. The ten top-ranked antiviral peptides were selected and docked to the SARS-CoV-2 main protease using GalaxyPepDock. Only the top docking scored candidate (AVP4) was further analyzed by molecular dynamics simulation for one nanosecond. According to the bioinformatic analysis results, the candidate SARS-CoV-2 main protease inhibitory peptides were 7–33 amino acid residues and formed hydrogen bonds at Thr22–24, Glu154, and Thr178 in domain 2 with short bonding distances. In addition, these top-ten candidate bioactive peptides contain hydrophilic amino acid residues and have a positive net charge. We hope that this study will provide a potential starting point for peptide-based therapeutic agents against COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emanating human infectious coronavirus that causes COVID-19 disease. On 11th March 2020, it has been announced as a pandemic by the World Health Organization (WHO). Recently, several repositioned drugs have been subjected to clinical investigations as anti-COVID-19 drugs. Here, in silico drug discovery tools were utilized to evaluate the binding affinities and features of eighteen anti-COVID-19 drug candidates against SARS-CoV-2 main protease (Mpro). Molecular docking calculations using Autodock Vina showed considerable binding affinities of the investigated drugs with docking scores ranging from − 5.3 to − 8.3 kcal/mol, with higher binding affinities for HIV drugs compared to the other antiviral drugs. Molecular dynamics (MD) simulations were performed for the predicted drug-Mpro complexes for 50 ns, followed by binding energy calculations utilizing molecular mechanics-generalized Born surface area (MM-GBSA) approach. MM-GBSA calculations demonstrated promising binding affinities of TMC-310911 and ritonavir towards SARS-CoV-2 Mpro, with binding energy values of − 52.8 and − 49.4 kcal/mol, respectively. Surpass potentialities of TMC-310911 and ritonavir are returned to their capabilities of forming multiple hydrogen bonds with the proximal amino acids inside Mpro's binding site. Structural and energetic analyses involving root-mean-square deviation, binding energy per-frame, center-of-mass distance, and hydrogen bond length demonstrated the stability of TMC-310911 and ritonavir inside the Mpro's active site over the 50 ns MD simulation. This study sheds light on HIV protease drugs as prospective SARS-CoV-2 Mpro inhibitors. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19), a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global health concern, as the World Health Organization declared this outbreak to be a global pandemic in March 2020. The need for an effective treatment is urgent because the development of an effective vaccine may take years given the complexity of the virus and its rapid mutation. One promising treatment target for COVID-19 is SARS-CoV-2 main protease. Thus, this study was aimed to examine whether Sulawesi propolis compounds produced by Tetragonula sapiens inhibit the enzymatic activity of SARS-CoV-2 main protease. In this study, molecular docking was performed to analyze the interaction profiles of propolis compounds with SARS-CoV-2 main protease. The results illustrated that two compounds, namely glyasperin A and broussoflavonol F, are potential drug candidates for COVID-19 based on their binding affinity of −7.8 kcal/mol and their ability to interact with His41 and Cys145 as catalytic sites. Both compounds also displayed favorable interaction profiles with SARS-CoV-2 main protease with binding similarities compared to inhibitor 13b as positive control 63% and 75% respectively.

In the search for new anti-HIV-1 agents, two forms of phenylamino-phenoxy-quinoline derivatives have been synthesized, namely, 2-phenylamino-4-phenoxy-quinoline and 6-phenylamino-4-phenoxy-quinoline. In this study, the binding interactions of phenylamino-phenoxy-quinoline derivatives and six commercially available drugs (hydroxychloroquine, ritonavir, remdesivir, S-217622, N3, and PF-07321332) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) were investigated using molecular docking and the ONIOM method. The molecular docking showed the hydrogen bonding and hydrophobic interactions of all the compounds in the pocket of SARS-CoV-2 main protease (Mpro), which plays an important role for the division and proliferation of the virus into the cell. The binding free energy values between the ligands and Mpro ranged from −7.06 to −10.61 kcal/mol. The molecular docking and ONIOM results suggested that 4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline and 4-(4′-cyanophenoxy)-2-(4″-cyanophenyl)-aminoquinoline have low binding energy values and appropriate molecular properties; moreover, both compounds could bind to Mpro via hydrogen bonding and Pi-Pi stacking interactions with amino acid residues, namely, HIS41, GLU166, and GLN192. These amino acids are related to the proteolytic cleavage process of the catalytic triad mechanisms. Therefore, this study provides important information for further studies on synthetic quinoline derivatives as antiviral candidates in the treatment of SARS-CoV-2.

Aim: SARS-coronavirus 2 main protease (Mpro) and host toll-like receptors (TLRs) were targeted to screen potential inhibitors among traditional antiviral medicinal plants. Materials & methods: LeDock software was adopted to determine the binding energy between candidate molecules and selected protein pockets. Enrichment analyses were applied to illustrate potential pharmacology networks of active molecules. Results: The citrus flavonoid rutin was identified to fit snugly into the Mpro substrate-binding pocket and to present a strong interaction with TLRs TLR2, TLR6 and TLR7. One-carbon metabolic process and nitrogen metabolism ranked high as potential targets toward rutin. Conclusion: Rutin may influence viral functional protein assembly and host inflammatory suppression. Its affinity for Mpro and TLRs render rutin a potential novel therapeutic anti-coronavirus strategy. [ABSTRACT FROM AUTHOR]

The coronavirus pandemic has affected more than 150 million people, while over 3.25 million people have died from the coronavirus disease 2019 (COVID-19). As there are no established therapies for COVID-19 treatment, drugs that inhibit viral replication are a promising target; specifically, the main protease (Mpro) that process CoV-encoded polyproteins serves as an Achilles heel for assembly of replication-transcription machinery as well as down-stream viral replication. In the search for potential antiviral drugs that target Mpro, a series of cembranoid diterpenes from the biologically active soft-coral genus Sarcophyton have been examined as SARS-CoV-2 Mpro inhibitors. Over 360 metabolites from the genus were screened using molecular docking calculations. Promising diterpenes were further characterized by molecular dynamics (MD) simulations based on molecular mechanics-generalized Born surface area (MM-GBSA) binding energy calculations. According to in silico calculations, five cembranoid diterpenes manifested adequate binding affinities as Mpro inhibitors with ΔGbinding < −33.0 kcal/mol. Binding energy and structural analyses of the most potent Sarcophyton inhibitor, bislatumlide A (340), was compared to darunavir, an HIV protease inhibitor that has been recently subjected to clinical-trial as an anti-COVID-19 drug. In silico analysis indicates that 340 has a higher binding affinity against Mpro than darunavir with ΔGbinding values of −43.8 and −34.8 kcal/mol, respectively throughout 100 ns MD simulations. Drug-likeness calculations revealed robust bioavailability and protein-protein interactions were identified for 340; biochemical signaling genes included ACE, MAPK14 and ESR1 as identified based on a STRING database. Pathway enrichment analysis combined with reactome mining revealed that 340 has the capability to re-modulate the p38 MAPK pathway hijacked by SARS-CoV-2 and antagonize injurious effects. These findings justify further in vivo and in vitro testing of 340 as an antiviral agent against SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for the COVID-19 pandemic, which generated more than 1.82 million deaths in 2020 alone, in addition to 83.8 million infections. Currently, there is no antiviral medication to treat COVID-19. In the search for drug leads, marine-derived metabolites are reported here as prospective SARS-CoV-2 inhibitors. Two hundred and twenty-seven terpene natural products isolated from the biodiverse Red-Sea ecosystem were screened for inhibitor activity against the SARS-CoV-2 main protease (Mpro) using molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area binding energy calculations. On the basis of in silico analyses, six terpenes demonstrated high potency as Mpro inhibitors with ΔGbinding ≤ −40.0 kcal/mol. The stability and binding affinity of the most potent metabolite, erylosides B, were compared to the human immunodeficiency virus protease inhibitor, lopinavir. Erylosides B showed greater binding affinity towards SARS-CoV-2 Mpro than lopinavir over 100 ns with ΔGbinding values of −51.9 vs. −33.6 kcal/mol, respectively. Protein–protein interactions indicate that erylosides B biochemical signaling shares gene components that mediate severe acute respiratory syndrome diseases, including the cytokine- and immune-signaling components BCL2L1, IL2, and PRKC. Pathway enrichment analysis and Boolean network modeling were performed towards a deep dissection and mining of the erylosides B target–function interactions. The current study identifies erylosides B as a promising anti-COVID-19 drug lead that warrants further in vitro and in vivo testing.

COVID-19 is a pandemic health emergency faced by the entire world. The clinical treatment of the severe acute respiratory syndrome (SARS) CoV-2 is currently based on the experimental administration of HIV antiviral drugs, such as lopinavir, ritonavir, and remdesivir (a nucleotide analogue used for Ebola infection). This work proposes a repurposing process using a database containing approximately 8000 known drugs in synergy structure- and ligand-based studies by means of the molecular docking and descriptor-based protocol. The proposed in silico findings identified new potential SARS CoV-2 main protease (MPRO) inhibitors that fit in the catalytic binding site of SARS CoV-2 MPRO. Several selected structures are NAD-like derivatives, suggesting a relevant role of these molecules in the modulation of SARS CoV-2 infection in conditions of cell chronic oxidative stress. Increased catabolism of NAD(H) during protein ribosylation in the DNA damage repair process may explain the greater susceptibility of the elderly population to the acute respiratory symptoms of COVID-19. The molecular modelling studies proposed herein agree with this hypothesis.

[Display omitted] • A series of lauroyl thymidine analogs were designed and synthesized. The chemical structures of these new thymidine analogs were confirmed by usual spectroscopic techniques. • In vitro antimicrobial activity was investigated against human and plant pathogenic organisms along with the prediction of activity spectra for substances (PASS). The incorporation of various aliphatic and aromatic groups in thymidine structure significantly increased the biological activity of synthesized analogs. • Molecular docking was performed on synthesized lauroyl-thymidine analogs against the main protease of SARS-CoV-2 and the analogs were found in strong interaction with the key Cys145 and His41 residues of the main protease. • The stability of the docked complex was confirmed by performing molecular dynamics which revealed that complex of lauroyl-thymidine and main protease were reported in improved dynamics stability as revealed by their uniform RMSD, RMSF, SASA, H-bond and RoG profiles. • Pharmacokinetic study revealed that the combination of toxicity prediction, in silico ADMET prediction, and drug-likeness had promising results because most of the synthesized thymidine analogs have improved kinetic parameters. • The POM analysis showed the presence of an antiviral (O1δ-, O2δ-) pharmacophore site. Nucleoside precursors and nucleoside analogs occupy an important place in the treatment of viral respiratory pathologies, especially during the current COVID-19 pandemic. From this perspective, the present study has been designed to explore and evaluate the synthesis and spectral characterisation of 5́- O- (lauroyl) thymidine analogs 2–6 with different aliphatic and aromatic groups through comprehensive in vitro antimicrobial screening, cytotoxicity assessment, physicochemical aspects, molecular docking and molecular dynamics analysis, along with pharmacokinetic prediction. A unimolar one-step lauroylation of thymidine under controlled conditions furnished the 5́- O- (lauroyl) thymidine and indicated the selectivity at C-5́ position and the development of thymidine based potential antimicrobial analogs, which were further converted into four newer 3́- O -(acyl)-5́- O -(lauroyl) thymidine analogs in reasonably good yields. The chemical structures of the newly synthesised analogs were ascertained by analysing their physicochemical, elemental, and spectroscopic data. In vitro antimicrobial tests against five bacteria and two fungi, along with the prediction of activity spectra for substances (PASS), indicated promising antibacterial functionality for these thymidine analogs compared to antifungal activity. In support of this observation, molecular docking experiments have been performed against the main protease of SARS-CoV-2, and significant binding affinities and non-bonding interactions were observed against the main protease (6LU7, 6Y84 and 7BQY), considering hydroxychloroquine (HCQ) as standard. Moreover, the 100 ns molecular dynamics simulation process was performed to monitor the behaviour of the complex structure formed by the main protease under in silico physiological conditions to examine its stability over time, and this revealed a stable conformation and binding pattern in a stimulating environment of thymidine analogs. Cytotoxicity determination confirmed that compounds were found less toxic. Pharmacokinetic predictions were investigated to evaluate their absorption, distribution, metabolism and toxic properties, and the combination of pharmacokinetic and drug-likeness predictions has shown promising results in silico. The POM analysis shows the presence of an antiviral (O1δ-, O2δ-) pharmacophore site. Overall, the current study should be of great help in the development of thymidine-based, novel, multiple drug-resistant antimicrobial and COVID-19 drugs. [ABSTRACT FROM AUTHOR]

• Folacin (Vitamin B9), Riboflavin (Vitamin B2), Phylloquinone oxide (Vitamin K1 oxide) and Ergocalciferol (Vitamin D2) are the structures with the best affinity in the biding site of studied enzyme: SARS-CoV-2 main protease. • Phylloquinone oxide and Folacin indicate that they may not fit very well in to the binding site. As expected, the Phylloquinone oxide exhibits small number of H-bonds with protein and Folacin does not form a good interaction with protein. • Riboflavin exhibits the highest number of Hydrogen bonds and forms consistent interactions with protein, which indicates that Riboflavin (Vitamin B2) could be interesting for the antiviral treatment of COVID-19. • Vitamin B2 respect the conditions mentioned in Lipinski's rule and have acceptable ADMET proprieties and this molecule would be much cheaper and simpler than the others drugs as a therapeutic option to be tested. COVID-19 is a new infectious disease caused by SARS-COV-2 virus of the coronavirus Family. The identification of drugs against this serious infection is a significant requirement due to the rapid rise in the positive cases and deaths around the world. With this concept, a molecular docking analysis for vitamins and their derivatives (28 molecules) with the active site of SARS-CoV-2 main protease was carried out. The results of molecular docking indicate that the structures with best binding energy in the binding site of the studied enzyme (lowest energy level) are observed for the compounds; Folacin, Riboflavin, and Phylloquinone oxide (Vitamin K1 oxide). A Molecular Dynamic simulation was carried out to study the binding stability for the selected vitamins with the active site of SARS-CoV-2 main protease enzyme. Molecular Dynamic shows that Phylloquinone oxide and Folacin are quite unstable in binding to SARS-CoV-2 main protease, while the Riboflavin is comparatively rigid. The higher fluctuations in Phylloquinone oxide and Folacin indicate that they may not fit very well into the binding site. As expected, the Phylloquinone oxide exhibits small number of H-bonds with protein and Folacin does not form a good interaction with protein. Riboflavin exhibits the highest number of Hydrogen bonds and forms consistent interactions with protein. Additionally, this molecule respect the conditions mentioned in Lipinski's rule and have acceptable ADMET proprieties which indicates that Riboflavin (Vitamin B2) could be interesting for the antiviral treatment of COVID-19. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] In the past two years, the COVID-19 pandemic has caused over 5 million deaths and 250 million infections worldwide. Despite successful vaccination efforts and emergency approval of small molecule therapies, a diverse range of antivirals is still needed to combat the inevitable resistance that will arise from new SARS-CoV-2 variants. The main protease of SARS-CoV-2 (Mpro) is an attractive drug target due to the clinical success of protease inhibitors against other viruses, such as HIV and HCV. However, in order to combat resistance, various chemical scaffolds need to be identified that have the potential to be developed into potent inhibitors. To this end, we screened a high-content protease inhibitor library against Mpro in vitro , in order to identify structurally diverse compounds that could be further developed into antiviral leads. Our high-content screening efforts retrieved 27 hits each with > 50% inhibition in our Mpro FRET assay. Of these, four of the top inhibitor compounds were chosen for follow-up due to their potency and drugability (Lipinski's rules of five criteria): anacardic acid, aloesin, aloeresin D, and TCID. Further analysis via dose response curves revealed IC 50 values of 6.8 μM, 38.9 μM, 125.3 μM, and 138.0 μM for each compound, respectively. Molecular docking studies demonstrated that the four inhibitors bound at the catalytic active site of Mpro with varying binding energies (-7.5 to −5.6 kcal/mol). Furthermore, Mpro FRET assay kinetic studies demonstrated that Mpro catalysis is better represented by a sigmoidal Hill model than the standard Michaelis-Menten hyperbola, indicating substantial cooperativity of the active enzyme dimer. This result suggests that the dimerization interface could be an attractive target for allosteric inhibitors. In conclusion, we identified two closely-related natural product compounds from the Aloe plant (aloesin and aloeresin D) that may serve as novel scaffolds for Mpro inhibitor design and additionally confirmed the strongly cooperative kinetics of Mpro proteolysis. These results further advance our knowledge of structure–function relationships in Mpro and offer new molecular scaffolds for inhibitor design. [ABSTRACT FROM AUTHOR]