An in silico approach to develop potential therapies against Middle East Respiratory Syndrome Coronavirus (MERS-CoV).

A deadly respiratory disease Middle East Respiratory Syndrome (MERS) is caused by a perilous virus known as MERS-CoV, which has a severe impact on human health. Currently, there is no approved vaccine, prophylaxis, or antiviral therapeutics for preventing MERS-CoV infection. Due to its inexorable and integral role in the maturation and replication of the MERS-CoV virus, the 3C-like protease is unavoidly a viable therapeutic target. In this study, 2369 phytoconstituents were enlisted from Japanese medicinal plants, and these compounds were screened against 3C-like protease to identify feasible inhibitors. The best three compounds were identified as Kihadanin B, Robustaflavone, and 3-beta-O- (trans-p-Coumaroyl) maslinic acid, with binding energies of -9.8, -9.4, and -9.2 kcal/mol, respectively. The top three potential candidates interacted with several active site residues in the targeted protein, including Cys145, Met168, Glu169, Ala171, and Gln192. The best three compounds were assessed by in silico technique to determine their drug-likeness properties, and they exhibited the least harmful features and the greatest drug-like qualities. Various descriptors, such as solvent-accessible surface area, root-mean-square fluctuation, root-mean-square deviation, hydrogen bond, and radius of gyration, validated the stability and firmness of the protein-ligand complexes throughout the 100ns molecular dynamics simulation. Moreover, the top three compounds exhibited better binding energy along with better stability and firmness than the inhibitor (Nafamostat), which was further confirmed by the binding free energy calculation. Therefore, this computational investigation could aid in the development of efficient therapeutics for life-threatening MERS-CoV infections.

Hydrogen-rich water: a key player in boosting wheat (Triticum aestivum L.) seedling growth and drought resilience.

In the modern world, wheat, a vital global cereal and the second most consumed, is vulnerable to climate change impacts. These include erratic rainfall and extreme temperatures, endangering global food security. Research on hydrogen-rich water (HRW) has gained momentum in plant and agricultural sciences due to its diverse functions. This study examined the effects of different HRW treatment durations on wheat, revealing that the 4-h treatment had the highest germination rate, enhancing potential, vigor, and germination indexes. This treatment also boosted relative water content, root and shoot weight, and average lengths. Moreover, the 4-h HRW treatment resulted in the highest chlorophyll and soluble protein concentrations in seeds while reducing cell death. The 4-h and 5-h HRW treatments significantly increased H2O2 levels, with the highest NO detected in both root and shoot after 4-h HRW exposure. Additionally, HRW-treated seeds exhibited increased Zn and Fe concentrations, along with antioxidant enzyme activities (CAT, SOD, APX) in roots and shoots. These findings suggest that HRW treatment could enhance wheat seed germination, growth, and nutrient absorption, thereby increasing agricultural productivity. Molecular analysis indicated significant upregulation of the Dreb1 gene with a 4-h HRW treatment. Thus, it shows promise in addressing climate change effects on wheat production. Therefore, HRW treatment could be a hopeful strategy for enhancing wheat plant drought tolerance, requiring further investigation (field experiments) to validate its impact on plant growth and drought stress mitigation.

Effects of gamma-radiation on microbial, nutritional, and functional properties of Katimon mango peels: A combined biochemical and in silico studies.

Gamma radiation has notable impacts on the flesh of mangoes. In this research, Katimon mangoes were subjected to different levels of irradiation (0.5, 1.0, 1.5, and 2.0 kGy) using a60Co irradiator. The results showed that irradiation significantly reduced the microbial population in the mango peels, with the 1.5 kGy dose showing the most significant reduction. Irradiation also delayed ripening and extended the shelf life of the mango peels. The total fat, protein, ash, moisture, and sugar content of the mango peels were all affected by irradiation. The total protein content, ash content and moisture content increased after irradiation, while the fat content remained relatively unchanged. The sugar content increased in all samples after storage, but the non-irradiated samples had higher sugar levels than the irradiated ones. The dietary fiber content of the mango peels was not significantly affected by irradiation. The vitamin C content decreased in all samples after storage. The titratable acidity and total soluble solids content of the mango peels increased after storage, but there were no significant differences between the irradiated and non-irradiated samples. Antioxidant activity and cytotoxicity assessment highlighted the antioxidant potential and reduced toxicity of irradiated samples. Additionally, the antimicrobial effectiveness of irradiated mango peels was evaluated. The most substantial inhibitory zones (measuring 16.90 ± 0.35) against Pseudomonas sp. were observed at a radiation dose of 1.5 kGy with 150 µg/disc. To identify potential antimicrobial agents, the volatile components of mangoes irradiated with 1.5 kGy were analyzed through GC-MS. Subsequently, these compounds were subjected to in silico studies against a viable protein, TgpA, of Pseudomonas sp. (PDB ID: 6G49). Based on molecular dynamic simulations and ADMET properties, (-)-Carvone (-6.2), p-Cymene (-6.1), and Acetic acid phenylmethyl ester (-6.1) were identified as promising compounds for controlling Pseudomonas sp.

Antioxidant, Cytotoxicity, Antimicrobial Activity, and In Silico Analysis of the Methanolic Leaf and Flower Extracts of Clitoria ternatea.

Infectious diseases pose a significant threat to human health worldwide. To address this challenge, we conducted a comprehensive study on the leaf and flower extracts of Clitoria ternatea plants. Our research encompassed in vitro assessments of their antibacterial, antibiofilm, antioxidant, and cytotoxic properties. Additionally, we employed in silico screening to identify promising compounds with potential applications in developing novel anti-Escherichia coli medications. Notably, our investigation revealed a remarkable inhibition zone of 13.00 ± 1 mm when applying the leaf extract (200 µg/ml) against E. coli, showcasing its potent antibacterial properties. Furthermore, both the leaf and flower extracts exhibited substantial biofilm inhibition efficacy against S. aureus, with inhibition percentages of 54% and 58%, respectively. In the realm of antioxidant activity, the leaf and flower extracts of C. ternatea displayed noteworthy DPPH free radical scavenging capabilities. Specifically, the leaf extract exhibited a substantial activity of 62.39% at a concentration of 150 µg/ml, while the flower extract achieved 44.08% at the same concentration. Our study also evaluated the impact on brine shrimp, where the floral extract displayed a significantly higher mortality rate of 93.33% at a dosage of 200 µg/ml compared to the leaf extract. To elucidate potential therapeutic targets, we utilized molecular docking techniques, focusing on the acbR protein (5ENR) associated with antibiotic resistance in E. coli. In this analysis, compounds isolated from the C. ternatea leaf extract, namely D1 (CID-14478556), D2 (CID-6423376), and D3 (CID-20393), exhibited binding energies of -8.2 kcal/mol, -6.5 kcal/mol, and -6.3 kcal/mol, respectively. Additionally, compounds from the flower extract, E1 (CID-5282761), E2 (CID-538757), and E3 (CID-536762), displayed binding energies of -5.4 kcal/mol, -5.3 kcal/mol, and -5.1 kcal/mol, respectively. In conclusion, the leaf and flower extracts derived from C. ternatea represent a promising natural resource with potential therapeutic applications in combating antibiotic-resistant pathogens.

Probiotic potential of Lactobacillus plantarum DMR14 for preserving and extending shelf life of fruits and fruit juice.

The harmful effects of chemical preservatives are driving the need for natural ones. To meet this demand, probiotic lactic acid bacteria (LAB) were isolated from fermented oats in this study. The goals of this study were to separate and identify probiotic LAB from fermented oats, to determine how effective these LAB are at combating pathogenic microorganisms in vitro, and to investigate their preservative capacity by applying the bacterium's cell-free supernatant (CFS) to specific fruits and fruit juice. The isolated strain was identified as Lactobacillus plantarum DMR14 using morphological, biochemical, and molecular investigation. Antimicrobial, antibiofilm, anti-oxidant, pH tolerance, and antibiotic resistance assays were used to evaluate the strain's probiotic potential, showing that Lactobacillus plantarum DMR14 had the strongest antagonistic and anti-biofilm capacity against Shigella boydii. Furthermore, the bacteriocin-containing compounds, cell-free supernatant (CFS) of the LAB, were tested against three fruits and one fruit juice, with the cell-free supernatant (CFS) of the bacterium lengthening the shelf life of the fruits compared to the untreated ones. Furthermore, while the concentration of coliform bacteria decreased in the treated sugarcane juice, an increase in the concentration of lactic acid bacteria suggested that the strain may be used as a fruit preservative in food industries.

In-silico prediction of highly promising natural fungicides against the destructive blast fungus Magnaporthe oryzae.

Magnaporthe oryzae causes destructive blast disease in more than 50 species of the major cereal crops rice, wheat and maize and destroys food of millions of people worldwide. Application of synthetic chemical fungicides are environmentally hazardous and unreliable in controlling M. oryzae. Conversely, naturally occurring biofungicides with multiple modes of actions are needed to be discovered for combatting the blast fungus. To find the effective biofungicides, we performed molecular docking study of some potential antifungal natural compounds targeting two proteins including a single-stranded DNA binding protein MoSub1 (4AGH), and an effector protein AVR-Pik (5E9G) of M. oryzae that regulates transcription in fungus and/or suppresses the host cell immunity. The thirty-nine natural compounds previously shown to inhibit M. oryzae growth and reproduction were put under molecular docking against these two proteins followed by simulation, free energy, and interaction analysis of protein-ligand complexes. The virtual screening revealed that two alkaloidal metabolites, camptothecin and GKK1032A2 showed excellent binding energy with any of these target proteins compared to reference commercial fungicides, azoxystrobin and strobilurin. Of the detected compounds, GKK1032A2 bound to both target proteins of M. oryzae. Both compounds showed excellent bioactivity scores as compared to the reference fungicides. Results of our computational biological study suggest that both camptothecin and GKK1032A2 are potential fungicides that could also be considered as lead compounds to design novel fungicides against the blast fungus. Furthermore, the GKK1032A2 acted as a multi-site mode of action fungicide against M. oryzae.

A Computational Study on Selected Alkaloids as SARS-CoV-2 Inhibitors: PASS Prediction, Molecular Docking, ADMET Analysis, DFT, and Molecular Dynamics Simulations.

Despite treatments and vaccinations, it remains difficult to develop naturally occurring COVID-19 inhibitors. Here, our main objective is to find potential lead compounds from the retrieved alkaloids with antiviral and other biological properties that selectively target the main SARS-CoV-2 protease (Mpro), which is required for viral replication. In this work, 252 alkaloids were aligned using Lipinski's rule of five and their antiviral activity was then assessed. The prediction of activity spectrum of substances (PASS) data was used to confirm the antiviral activities of 112 alkaloids. Finally, 50 alkaloids were docked with Mpro. Furthermore, assessments of molecular electrostatic potential surface (MEPS), density functional theory (DFT), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) were performed, and a few of them appeared to have potential as candidates for oral administration. Molecular dynamics simulations (MDS) with a time step of up to 100 ns were used to confirm that the three docked complexes were more stable. It was found that the most prevalent and active binding sites that limit Mpro'sactivity are PHE294, ARG298, and GLN110. All retrieved data were compared to conventional antivirals, fumarostelline, strychnidin-10-one (L-1), 2,3-dimethoxy-brucin (L-7), and alkaloid ND-305B (L-16) and were proposed as enhanced SARS-CoV-2 inhibitors. Finally, with additional clinical or necessary study, it may be able to use these indicated natural alkaloids or their analogs as potential therapeutic candidates.

Integrated Computational Approaches for Inhibiting Sex Hormone-Binding Globulin in Male Infertility by Screening Potent Phytochemicals.

Male infertility is significantly influenced by the plasma-protein sex hormone-binding globulin (SHBG). Male infertility, erectile dysfunction, prostate cancer, and several other male reproductive system diseases are all caused by reduced testosterone bioavailability due to its binding to SHBG. In this study, we have identified 345 phytochemicals from 200 literature reviews that potentially inhibit severe acute respiratory syndrome coronavirus 2. Only a few studies have been done using the SARS-CoV-2 inhibitors to identify the SHBG inhibitor, which is thought to be the main protein responsible for male infertility. In virtual-screening and molecular-docking experiments, cryptomisrine, dorsilurin E, and isoiguesterin were identified as potential SHBG inhibitors with binding affinities of -9.2, -9.0, and -8.8 kcal/mol, respectively. They were also found to have higher binding affinities than the control drug anastrozole (-7.0 kcal/mol). In addition to favorable pharmacological properties, these top three phytochemicals showed no adverse effects in pharmacokinetic evaluations. Several molecular dynamics simulation profiles' root-mean-square deviation, radius of gyration, root-mean-square fluctuation, hydrogen bonds, and solvent-accessible surface area supported the top three protein-ligand complexes' better firmness and stability than the control drug throughout the 100 ns simulation period. These combinatorial drug-design approaches indicate that these three phytochemicals could be developed as potential drugs to treat male infertility.

Klebsiella pneumoniae Volatile Organic Compounds (VOCs) Protect Artemia salina from Fish Pathogen Aeromonas sp.: A Combined In Vitro, In Vivo, and In Silico Approach.

Antibiotic resistance is an alarming threat all over the world, and the biofilm formation efficacy of bacteria is making the situation worse. The antagonistic efficacy of Klebsiella pneumoniae against one of the known fish pathogens, Aeromonas sp., is examined in this study. Moreover, Aeromonas sp.'s biofilm formation ability and in vivo pathogenicity on Artemia salina are also justified here. Firstly, six selected bacterial strains were used to obtain antimicrobial compounds against this pathogenic strain. Among those, Klebsiella pneumoniae, another pathogenic bacterium, surprisingly demonstrated remarkable antagonistic activity against Aeromonas sp. in both in vitro and in vivo assays. The biofilm distrusting potentiality of Klebsiella pneumoniae's cell-free supernatants (CFSs) was likewise found to be around 56%. Furthermore, the volatile compounds of Klebsiella pneumoniae were identified by GC-MS in order to explore compounds with antibacterial efficacy against Aeromonas sp. through an in silico study, where 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) (PDB: 5B7P) was chosen as a target protein for its unique characteristics and pathogenicity. Several volatile compounds, such as oxime- methoxy-phenyl-, fluoren-9-ol, 3,6-dimethoxy-9-(2-phenylethynyl)-, and 2H-indol-2-one, 1,3-dihydro- showed a strong binding affinity, with free energy of -6.7, -7.1, and -6.4 Kcal/mol, respectively, in complexes with the protein MTAN. Moreover, the root-mean-square deviation, solvent-accessible surface area, radius of gyration, root-mean-square fluctuations, and hydrogen bonds were used to ensure the binding stability of the docked complexes in the atomistic simulation. Thus, Klebsiella pneumoniae and its potential compounds can be employed as an alternative to antibiotics for aquaculture, demonstrating their effectiveness in suppressing Aeromonas sp.

Cell-Free Supernatants (CFSs) from the Culture of Bacillus subtilis Inhibit Pseudomonas sp. Biofilm Formation.

Biofilm inhibition has been identified as a novel drug target for the development of broad-spectrum antibiotics to combat infections caused by drug-resistant bacteria. Although several plant-based compounds have been reported to have anti-biofilm properties, research on the anti-biofilm properties of bacterial bioactive compounds has been sparse. In this study, the efficacy of compounds from a cell-free supernatant of Bacillus subtilis against a biofilm formation of Pseudomonas sp. was studied through in vitro, in vivo and in silico studies. Here, in well diffusion method, Bacillus subtilis demonstrated antibacterial activity, and more than 50% biofilm inhibition activity against Pseudomonas sp. was exhibited through in vitro studies. Moreover, molecular docking and molecular dynamics (MD) simulation gave insights into the possible mode of action of the bacterial volatile compounds identified through GC-MS to inhibit the biofilm-formation protein (PDB ID: 7M1M) of Pseudomonas sp. The binding energy revealed from docking studies ranged from -2.3 to -7.0 kcal mol-1. Moreover, 1-(9H-Fluoren-2-yl)-2-(1-phenyl-1H-ttetrazole5-ylsulfanyl)-ethanone was found to be the best-docked compound through ADMET and pharmacokinetic properties. Furthermore, MD simulations further supported the in vitro studies and formed a stable complex with the tested protein. Thus, this study gives an insight into the development of new antibiotics to combat multi-drug-resistant bacteria.

Biological Efficacy of Compounds from Stingless Honey and Sting Honey against Two Pathogenic Bacteria: An In Vitro and In Silico Study.

Honey inhibits bacterial growth due to the high sugar concentration, hydrogen peroxide generation, and proteinaceous compounds present in it. In this study, the antibacterial activity of stingless and sting honey against foodborne pathogenic bacteria isolated from spoiled milk samples was examined. The isolated bacterial strains were confirmed as Bacillus cereus and Listeriamonocytogenes through morphological, biochemical, and 16 s RNA analysis. Physiochemical characterizations of the honey samples revealed that both of the honey samples had an acidic pH, low water content, moderate reducing sugar content, and higher proline content. Through the disc diffusion method, the antibacterial activities of the samples were assayed and better results were observed for the 50 mg/disc honey. Both stingless and sting honey showed the most positive efficacy against Bacillus cereus. Therefore, an in silico study was conducted against this bacterium with some common compounds of honey. From several retrieved constituents of stingless and sting honey, 2,4-dihydroxy-2,5-dimethyl 3(2H)-furan-3-one (furan) and 4H-pyran-4-one,2,3-dihydro of both samples and beta.-D-glucopyranose from the stingless revealed high ligand-protein binding efficiencies for the target protein (6d5z, hemolysin II). The root-mean-square deviation, solvent-accessible surface area, the radius of gyration, root-mean-square fluctuations, and hydrogen bonds were used to ensure the binding stability of the docked complexes in the atomistic simulation and confirmed their stability. The combined effort of wet and dry lab-based work support, to some extent, that the antimicrobial properties of honey have great potential for application in medicine as well as in the food industries.

Plant-derived compounds effectively inhibit the main protease of SARS-CoV-2: An in silico approach.

The current coronavirus disease 2019 (COVID-19) pandemic, caused by the coronavirus 2 (SARS-CoV-2), involves severe acute respiratory syndrome and poses unprecedented challenges to global health. Structure-based drug design techniques have been developed targeting the main protease of the SARS-CoV-2, responsible for viral replication and transcription, to rapidly identify effective inhibitors and therapeutic targets. Herein, we constructed a phytochemical dataset of 1154 compounds using deep literature mining and explored their potential to bind with and inhibit the main protease of SARS-CoV-2. The three most effective phytochemicals Cosmosiine, Pelargonidin-3-O-glucoside, and Cleomiscosin A had binding energies of -8.4, -8.4, and -8.2 kcal/mol, respectively, in the docking analysis. These molecules could bind to Gln189, Glu166, Cys145, His41, and Met165 residues on the active site of the targeted protein, leading to specific inhibition. The pharmacological characteristics and toxicity of these compounds, examined using absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses, revealed no carcinogenicity or toxicity. Furthermore, the complexes were simulated with molecular dynamics for 100 ns to calculate the root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen profiles from the simulation trajectories. Our analysis validated the rigidity of the docked protein-ligand. Taken together, our computational study findings might help develop potential drugs to combat the main protease of the SARS-CoV-2 and help alleviate the severity of the pandemic.

Use of Next-Generation Sequencing for Identifying Mitochondrial Disorders.

Mitochondria are major contributors to ATP synthesis, generating more than 90% of the total cellular energy production through oxidative phosphorylation (OXPHOS): metabolite oxidation, such as the ß-oxidation of fatty acids, and the Krebs's cycle. OXPHOS inadequacy due to large genetic lesions in mitochondrial as well as nuclear genes and homo- or heteroplasmic point mutations in mitochondrially encoded genes is a characteristic of heterogeneous, maternally inherited genetic disorders known as mitochondrial disorders that affect multisystemic tissues and organs with high energy requirements, resulting in various signs and symptoms. Several traditional diagnostic approaches, including magnetic resonance imaging of the brain, cardiac testing, biochemical screening, variable heteroplasmy genetic testing, identifying clinical features, and skeletal muscle biopsies, are associated with increased risks, high costs, a high degree of false-positive or false-negative results, or a lack of precision, which limits their diagnostic abilities for mitochondrial disorders. Variable heteroplasmy levels, mtDNA depletion, and the identification of pathogenic variants can be detected through genetic sequencing, including the gold standard Sanger sequencing. However, sequencing can be time consuming, and Sanger sequencing can result in the missed recognition of larger structural variations such as CNVs or copy-number variations. Although each sequencing method has its own limitations, genetic sequencing can be an alternative to traditional diagnostic methods. The ever-growing roster of possible mutations has led to the development of next-generation sequencing (NGS). The enhancement of NGS methods can offer a precise diagnosis of the mitochondrial disorder within a short period at a reasonable expense for both research and clinical applications.

The Emergence of SARS-CoV-2 Variants With a Lower Antibody Response: A Genomic and Clinical Perspective.

The emergence of several novel SARS-CoV-2 variants regarded as variants of concern (VOCs) has exacerbated pathogenic and immunologic prominences, as well as reduced diagnostic sensitivity due to phenotype modification-capable mutations. Furthermore, latent and more virulent strains that have arisen as a result of unique mutations with increased evolutionary potential represent a threat to vaccine effectiveness in terms of incoming and existing variants. As a result, resisting natural immunity, which leads to higher reinfection rates, and avoiding vaccination-induced immunization, which leads to a lack of vaccine effectiveness, has become a crucial problem for public health around the world. This study attempts to review the genomic variation and pandemic impact of emerging variations of concern based on clinical characteristics management and immunization effectiveness. The goal of this study is to gain a better understanding of the link between genome level polymorphism, clinical symptom manifestation, and current vaccination in the instance of VOCs.

phytochemdb: a platform for virtual screening and computer-aided drug designing.

The phytochemicals of medicinal plants are regarded as a rich source of diverse chemical spaces that have been used as supplements and alternative medicines in the millennium. Even in this era of combinatorial chemical drugs, phytomedicines account for a large share of the statistics of newly approved drugs. In the field of computational aided and rational drug design, there is an urgent need to develop and build a useful phytochemical database management system with a user-friendly interface that allows proper data storage, retrieval and management. We showed 'phytochemdb', a manually managed database that compiles 525 plants and their corresponding 8093 phytochemicals, aiming to incorporate the activities of phytochemicals from medicinal plants. The database collects molecular formula, three-dimensional/two-dimensional structure, canonical SMILES, molecular weight, no. of heavy atoms, no. of aromatic heavy atoms, fraction Csp3, no. of rotatable bonds, no. of H-bond acceptors, no. of H-bond donors, molar refractivity, topological polar surface area, gastrointestinal absorption, Blood-Brain Barrier (BBB) permeant, P-gp substrate, CYP1A2 inhibitor, CYP2C19 inhibitor, CYP2C9 inhibitor, CYP2D6 inhibitor, CYP3A4 inhibitor, Log Kp, Ghose, Veber, Egan, Muegge, bioavailability scores, pan-assay interference compounds, Brenk, Leadlikeness, synthetic accessibility, iLOGP and Lipinski rule of five with the number of violations for each compound. It provides open contribution functions for the researchers who screen phytochemicals in the laboratory and have released their data. 'phytochemdb' is a comprehensive database that gathers most of the information about medicinal plants in one platform, which is considered to be very beneficial to the work of researchers on medicinal plants. 'phytochemdb' is available for free at https://phytochemdb.com/.

Computational screening and biochemical analysis of Pistacia integerrima and Pandanus odorifer plants to find effective inhibitors against Receptor-Binding domain (RBD) of the spike protein of SARS-Cov-2.

Although World Health Organization-approved emergency vaccines are available in many countries, the mortality rate from COVID-19 remains high due to the fourth or fifth wave and the delta variant of the coronavirus. Thus, an effective mechanistic investigation in treating this disease is urgently needed. In this work, we extracted phytochemicals from two mangrove plants, Pistacia integerrima and Pandanus odorifer, assessing their potential actions against the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2. The antioxidant activities of Pistacia integerrima leaves and fruits were 142.10 and 97.13 µg/mL, respectively, whereas Pandanus odorifer leaves and fruits were 112.50 and 292.71 µg/mL, respectively. Furthermore, leaf extracts from both plants had lower cytotoxicity against Artemia salina than fruit extracts. Gas chromatography-mass spectrometry analysis revealed a total of 145 potential phytochemicals from these extracts. Three phytochemicals, 28-demethyl-beta-amyrone, 24-Noroleana-3,12-diene, and stigmasterol, displayed binding free energy values of - 8.3, -7.5, and - 8.1 Kcal/mol, respectively, in complexes with the spike protein of SARS-CoV-2. The root-mean-square deviation, solvent-accessible surface area, radius of gyration, root-mean-square fluctuations, and hydrogen bonds were used to ensure the binding stability of the docked complexes in the atomistic simulation. Thus, wet-lab validations are necessary to support these findings.

Antiviral peptides against the main protease of SARS-CoV-2: A molecular docking and dynamics study.

The recent coronavirus outbreak has changed the world's economy and health sectors due to the high mortality and transmission rates. Because the development of new effective vaccines or treatments against the virus can take time, an urgent need exists for the rapid development and design of new drug candidates to combat this pathogen. Here, we obtained antiviral peptides obtained from the data repository of antimicrobial peptides (DRAMP) and screened their predicted tertiary structures for the ability to inhibit the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using multiple combinatorial docking programs, including PatchDock, FireDock, and ClusPro. The four best peptides, DRAMP00877, DRAMP02333, DRAMP02669, and DRAMP03804, had binding energies of -1125.3, -1084.5, -1005.2, and -924.2 Kcal/mol, respectively, as determined using ClusPro, and binding energies of -55.37, -50.96, -49.25, -54.81 Kcal/mol, respectively, as determined using FireDock, which were better binding energy values than observed for other peptide molecules. These peptides were found to bind with the active cavity of the SARS-CoV-2 main protease; at Glu166, Cys145, Asn142, Phe140, and Met165, in addition to the substrate-binding sites, Domain 2 and Domain 3, whereas fewer interactions were observed with Domain 1. The docking studies were further confirmed by a molecular dynamics simulation study, in which several descriptors, including the root-mean-square difference (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), radius of gyration (Rg), and hydrogen bond formation, confirmed the stable nature of the peptide-main protease complexes. Toxicity and allergenicity studies confirmed the non-allergenic nature of the peptides. This present study suggests that these identified antiviral peptide molecules might inhibit the main protease of SARS-CoV-2, although further wet-lab experiments remain necessary to verify these findings.

Molecular docking and dynamics study to explore phytochemical ligand molecules against the main protease of SARS-CoV-2 from extensive phytochemical datasets.

BACKGROUND: The high transmission and pathogenicity of SARS-CoV-2 has led to a pandemic that has halted the world's economy and health. The newly evolved strains and scarcity of vaccines has worsened the situation. The main protease (Mpro) of SARS-CoV-2 can act as a potential target due to its role in viral replication and conservation level. METHODS: In this study, we have enlisted more than 1100 phytochemicals from Asian plants based on deep literature mining. The compounds library was screened against the Mpro of SARS-CoV-2. RESULTS: The selected three ligands, Flemichin, Delta-Oleanolic acid, and Emodin 1-O-beta-D-glucoside had a binding energy of -8.9, -8.9, -8.7 KJ/mol respectively. The compounds bind to the active groove of the main protease at; Cys145, Glu166, His41, Met49, Pro168, Met165, Gln189. The multiple descriptors from the simulation study; root mean square deviation, root mean square fluctuation, radius of gyration, hydrogen bond, solvent accessible surface area confirms the stable nature of the protein-ligand complexes. Furthermore, post-md analysis confirms the rigidness in the docked poses over the simulation trajectories. CONCLUSIONS: Our combinatorial drug design approaches may help researchers to identify suitable drug candidates against SARS-CoV-2.

Designing a multi-epitope vaccine candidate to combat MERS-CoV by employing an immunoinformatics approach.

Currently, no approved vaccine is available against the Middle East respiratory syndrome coronavirus (MERS-CoV), which causes severe respiratory disease. The spike glycoprotein is typically considered a suitable target for MERS-CoV vaccine candidates. A computational strategy can be used to design an antigenic vaccine against a pathogen. Therefore, we used immunoinformatics and computational approaches to design a multi-epitope vaccine that targets the spike glycoprotein of MERS-CoV. After using numerous immunoinformatics tools and applying several immune filters, a poly-epitope vaccine was constructed comprising cytotoxic T-cell lymphocyte (CTL)-, helper T-cell lymphocyte (HTL)-, and interferon-gamma (IFN-γ)-inducing epitopes. In addition, various physicochemical, allergenic, and antigenic profiles were evaluated to confirm the immunogenicity and safety of the vaccine. Molecular interactions, binding affinities, and the thermodynamic stability of the vaccine were examined through molecular docking and dynamic simulation approaches, during which we identified a stable and strong interaction with Toll-like receptors (TLRs). In silico immune simulations were performed to assess the immune-response triggering capabilities of the vaccine. This computational analysis suggested that the proposed vaccine candidate would be structurally stable and capable of generating an effective immune response to combat viral infections; however, experimental evaluations remain necessary to verify the exact safety and immunogenicity profile of this vaccine.

Plant-Based Phytochemical Screening by Targeting Main Protease of SARS-CoV-2 to Design Effective Potent Inhibitors.

Currently, a worldwide pandemic has been declared in response to the spread of coronavirus disease 2019 (COVID-19), a fatal and fast-spreading viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The low availability of efficient vaccines and treatment options has resulted in a high mortality rate, bringing the world economy to its knees. Thus, mechanistic investigations of drugs capable of counteracting this disease are in high demand. The main protease (Mpro) expressed by SARS-CoV-2 has been targeted for the development of potential drug candidates due to the crucial role played by Mpro in viral replication and transcription. We generated a phytochemical library containing 1672 phytochemicals derived from 56 plants, which have been reported as having antiviral, antibacterial, and antifungal activity. A molecular docking program was used to screen the top three candidate compounds: epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate, which had respective binding affinities of -8.4, -8.5, and -8.8 kcal/mol. Several active sites in the targeted protein, including Cys145, His41, Met49, Glu66, and Met165, were found to interact with the top three candidate compounds. The multiple simulation profile, root-mean-square deviation, root-mean-square fluctuation, radius of gyration, and solvent-accessible surface area values supported the inflexible nature of the docked protein-compound complexes. The toxicity and carcinogenicity profiles were assessed, which showed that epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate had favorable pharmacological properties with no adverse effects. These findings suggest that these compounds could be developed as part of an effective drug development pathway to treat COVID-19.