SARS-CoV-2 main protease inhibition by compounds isolated from Luffa cylindrica using molecular docking.
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ABSTRACT:
SUBMITTER: Cao TQ
PROVIDER: S-EPMC7977011 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has adversely affected global health since its emergence in 2019. The lack of effective treatments prompted worldwide efforts to immediately develop therapeutic strategies against COVID-19. The main protease (Mpro) of SARS-CoV-2 plays a crucial role in viral replication, and therefore it serves as an attractive target for COVID-19-specific drug development. Due to the richness and diversity of insect protease inhibitors, we docked SARS-CoV-2 Mpro onto 25 publicly accessible insect-derived protease inhibitors using the ClusPro server, and the regions with high inhibitory potentials against Mpro were used to design peptides. Interactions of these inhibitory peptides with Mpro were further assessed by two directed docking programs, AutoDock and Haddock. AutoDock analysis predicted the highest binding energy (-9.39 kcal/mol) and the lowest inhibition constant (130 nM) for the peptide 1KJ0-7 derived from SGCI (Schistocerca gregaria chymotrypsin inhibitor). On the other hand, Haddock analysis resulted in the discovery of a different peptide designated 2ERW-9 from infestin, a serine protease inhibitor of Triatoma infestans, with the best docking score (-131), binding energy (-11.7 kcal/mol), and dissociation constant (2.6E-09 M) for Mpro. Furthermore, using molecular dynamic simulations, 1KJ0-7 and 2ERW-9 were demonstrated to form stable complexes with Mpro. The peptides also showed suitable drug-likeness properties compared to commercially available drugs based on Lipinski's rule. Our findings present two peptides with possible protease inhibitor activities against Mpro and further demonstrate the potential of insect-derived peptides and computer-aided methods for drug discovery.
| S-EPMC8755557 | biostudies-literature
Project description:The recently emerged 2019 Novel Coronavirus (SARS-CoV-2) and associated COVID-19 disease cause serious or even fatal respiratory tract infection and yet no approved therapeutics or effective treatment is currently available to effectively combat the outbreak. This urgent situation is pressing the world to respond with the development of novel vaccine or a small molecule therapeutics for SARS-CoV-2. Along these efforts, the structure of SARS-CoV-2 main protease (Mpro) has been rapidly resolved and made publicly available to facilitate global efforts to develop novel drug candidates. Recently, our group has developed a novel deep learning platform - Deep Docking (DD) which provides fast prediction of docking scores of Glide (or any other docking program) and, hence, enables structure-based virtual screening of billions of purchasable molecules in a short time. In the current study we applied DD to all 1.3 billion compounds from ZINC15 library to identify top 1,000 potential ligands for SARS-CoV-2 Mpro protein. The compounds are made publicly available for further characterization and development by scientific community.
| S-EPMC7228259 | biostudies-literature
Project description:The study aims to evaluate the potency of two hundred natural antiviral phytocompounds against the active site of the Severe Acquired Respiratory Syndrome - Coronavirus - 2 (SARS-CoV-2) Main-Protease (Mpro) using AutoDock 4.2.6. The three- dimensional crystal structure of the Mpro (PDB Id: 6LU7) was retrieved from the Protein Data Bank (PDB), the active site was predicted using MetaPocket 2.0. Food and Drug Administration (FDA) approved viral protease inhibitors were used as standards for comparison of results. The compounds theaflavin-3-3'-digallate, rutin, hypericin, robustaflavone, and (-)-solenolide A with respective binding energy of -12.41 (Ki = 794.96 pM); -11.33 (Ki = 4.98 nM); -11.17 (Ki = 6.54 nM); -10.92 (Ki = 9.85 nM); and -10.82 kcal/mol (Ki = 11.88 nM) were ranked top as Coronavirus Disease - 2019 (COVID-19) Mpro inhibitors. The interacting amino acid residues were visualized using Discovery Studio 3.5 to elucidate the 2-dimensional and 3-dimensional interactions. The study was validated by i) re-docking the N3-peptide inhibitor-Mpro and superimposing them onto co-crystallized complex and ii) docking decoy ligands to Mpro. The ligands that showed low binding energy were further predicted for and pharmacokinetic properties and Lipinski's rule of 5 and the results are tabulated and discussed. Molecular dynamics simulations were performed for 50 ns for those compounds using the Desmond package, Schrödinger to assess the conformational stability and fluctuations of protein-ligand complexes during the simulation. Thus, the natural compounds could act as a lead for the COVID-19 regimen after in-vitro and in- vivo clinical trials.Communicated by Ramaswamy H. Sarma.
| S-EPMC7573242 | biostudies-literature
Project description:Background/aimSARS-CoV-2 is one of the coronavirus families that emerged at the end of 2019. It infected the respiratory system and caused a pandemic worldwide. Fluoroquinolones (FQs) have been safely used as antibacterial agents for decades. The antiviral activity of FQs was observed. Moreover, substitution on the C-7 position of ciprofloxacin enhanced its antiviral activity. Therefore, this study aims to investigate the antiviral activity of 7-(4-(N-substituted-carbamoyl-methyl)piperazin-1yl)-chalcone in comparison with ciprofloxacin against SARS-CoV-2 main protease (Mpro ).Materials and methodsVero cells were infected with SARS-CoV-2. After treatment with ciprofloxacin and the chalcone at the concentrations of 1.6, 16, 160 nmol/L for 48 h, SARS-CoV-2 viral load was detected using real-time qPCR, SARS-CoV-2 infectivity was determined using plaque assay, and the main protease enzyme activity was detected using in vitro 3CL-protease inhibition assay. The activity of the chalcone was justified through molecular docking within SARS-CoV-2 Mpro , in comparison with ciprofloxacin.ResultsThe new chalcone significantly inhibited viral load replication where the EC50 was 3.93 nmol/L, the plaque formation ability of the virus was inhibited to 86.8% ± 2.47. The chalcone exhibited a significant inhibitory effect against SARS-CoV-2 Mpro in vitro in a dose-dependent manner. The docking study into SARS-CoV-2 Mpro active site justified the importance of adding a substitution to the parent drug. Additionally, the assessment of the drug-likeness properties indicated that the chalcone might have acceptable ADMET properties.ConclusionThe new chalcone might be useful and has new insights for the inhibition of SARS-CoV-2 Mpro .
| S-EPMC8444764 | biostudies-literature
Project description:COVID-19 as per early April 2021, has globally exceeded 129 million cases and is the cause of about 2.8 million deaths. Since the illness is known to have a wide array of symptoms, in addition to its ability to spread rapidly through contact and the complexity involved in developing drugs, there is an immediate need to look into alternative treatment regimes. This study was intended to identify potential antiviral compounds from Moringa oleifera against the selected target main protease (Mpro), which is vital for the survival of the virus. In silico molecular docking and dynamics was performed to determine a potential inhibitor against Mpro. Phytochemicals of Moringa olifera reported in literature were retrieved from public databases and employed for molecular docking studies against Mpro. PyRx software was used to perform docking analysis. Visualization of amino acid interactions between the ligand and target was performed using Maestro and Discovery studio visualizer to analyze the type of interactions. Compounds displaying high binding affinities were subjected for analysis of pharmacokinetic studies, later molecular dynamics (MD) and MM-PBSA studies was conducted over selected compounds using GROMACS. Rutin and Isorhamnetin-3-O-rutinoside, both flavonoids thoroughly studied for their medicinal properties showcased strong interactions and the highest binding affinity of −8.9 kcal/mol with the Mpro. The binding energy calculated employing MM-PBSA for Rutin and Isorhamnetin-3-O-rutinoside were −86.832 kJ/mol and −72.984 kJ/mol, respectively. The overall studies revealed that Rutin and Isorhamnetin-3-O-rutinoside are portenial in inhibiting the SARS-CoV-2 Mpro and can be validated through in-vitro and in-vivo studies.
| S-EPMC8547798 | biostudies-literature
Project description:In an analysis of the structural stability of the coronavirus main protease (Mpro), we identified regions of the protein that could be disabled by cobalt(III)-cation binding to histidines and cysteines [1]. Here we have extended our work to include copper(II) chelates, which we have docked to HIS 41 and CYS 145 in the Mpro active-site region. We have found stable docked structures where Cu(II) could readily bond to the CYS 145 thiolate, which would be lethal to the enzyme. We also started studying the Spike Protein, PDB ID: 6VXX and the region around the D614G mutant.
| S-EPMC7668746 | biostudies-literature
Project description:BackgroundDue to the migratory flow of infected people with severe acute respiratory syndrome virus (SARS COV-2), the number of confirmed cases of coronavirus disease 2019 (COVID-19) is accelerating globally; preclinical evidence of antiviral agents that can combat this pandemic is still elusive. We identified published articles on SARS-COV efficacy experiments in which some selected compounds were used to test the reduction of the virus load in mice.MethodsA systematic search of articles was conducted in PubMed, Web of Science, and Scopus. We then developed a combined model based on a systematic review, meta-analyses, and molecular docking studies to evaluate the effect size of preclinical studies of compounds that have been tested against SARS-COV. Because substantial heterogeneity was expected, random effect model meta-analyses were carried out to estimate the overall pooled disease's prevalence. All meta-analyses were performed with Stata version 15.0. Subgroup analyses on therapies were conducted as well. Molecular docking studies of the inhibitors in the active pocket of COVID-19 protease were also performed.ResultsFrom all screened articles, six studies were appropriate for ultimate meta-analysis and systematic review. The residual amount of heterogeneity was high (τ2 =0.02; heterogeneity I2 =85.5 % with heterogeneity chi-square =103.57, a degree of freedom =15, and p <0.001). The overall random pooled prevalence of infected mice treated with the selected compounds was 78.1 % [95 % Confidence Interval (CI): 14.7-17.0 %]. Prophylactic has a significantly higher pooled prevalence than therapeutic, with 21.8 % (95 % CI: 16.4 % to 28.8 %). Our results indicated that most of the SARS-COV inhibitors analyzed were less effective in reducing the lung virus titer of SARS-COV infection in animal models. The findings from molecular docking studies also identified COVID-19 inhibitors that are good for optimization and drug development to fight against COVID-19 infection.ConclusionsFindings from the review showed that studies on the preclinical compounds targeting SARS-COV and COVID-19 are limited. Furthermore, molecular docking studies and meta-analysis results substantiated three compounds, i.e., EIDD-2801, GS-5734, and amodiaquine. HIPPOKRATIA 2020, 24(3): 99-106.
| S-EPMC8256780 | biostudies-literature
Project description:SARS-CoV-2 has rapidly emerged as a global pandemic with high infection rate. At present, there is no drug available for this deadly disease. Recently, Mpro (Main Protease) enzyme has been identified as essential proteins for the survival of this virus. In the present work, Lipinski's rules and molecular docking have been performed to identify plausible inhibitors of Mpro using food compounds. For virtual screening, a database of food compounds was downloaded and then filtered using Lipinski's rule of five. Then, molecular docking was accomplished to identify hits using Mpro protein as the target enzyme. This led to identification of a Spermidine derivative as a hit. In the next step, Spermidine derivatives were collected from PubMed and screened for their binding with Mpro protein. In addition, molecular dynamic simulations (200 ns) were executed to get additional information. Some of the compounds are found to have strong affinity for Mpro, therefore these hits could be used to develop a therapeutic agent for SARS-CoV-2.
| S-EPMC8295492 | biostudies-literature
Project description:Newly emerged SARS-CoV-2 made recent pandemic situations across the globe is accountable for countless unwanted death and insufferable panic associated with co-morbidities among mass people. The scarcity of appropriate medical treatment and no effective vaccine or medicine against SARS-CoV-2 has turned the situation worst. Therefore, in this study, we made a deep literature review to enlist plant-derived natural compounds and considered their binding mechanism with the main protease of SARS-CoV-2 through combinatorial bioinformatics approaches. Among all, a total of 14 compounds were filtered where Carinol, Albanin, Myricetin were had better binding profile than the rest of the compounds with having binding energy of -8.476, -8.036, -8.439 kcal/mol, respectively. Furthermore, MM-GBSA calculations were also considered in this selection process to support docking studies. Besides, 100 ns molecular dynamics simulation endorsed the rigid nature, less conformational variation and binding stiffness. As this study, represents a perfect model for SARS-CoV-2 main protease inhibition through bioinformatics study, these potential drug candidates may assist the researchers to find a superior and effective solution against COVID-19 after future experiments.Communicated by Ramaswamy Sarma.
| S-EPMC7441771 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19) has emerged from China and globally affected the entire population through the human-to-human transmission of a newly emerged virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The genome of SARS-CoV-2 encodes several proteins that are essential for multiplication and pathogenesis. The main protease (Mpro or 3CLpro) of SARS-CoV-2 plays a central role in its pathogenesis and thus is considered as an attractive drug target for the drug design and development of small-molecule inhibitors. We have employed an extensive structure-based high-throughput virtual screening to discover potential natural compounds from the ZINC database which could inhibit the Mpro of SARS-CoV-2. Initially, the hits were selected on the basis of their physicochemical and drug-like properties. Subsequently, the PAINS filter, estimation of binding affinities using molecular docking, and interaction analyses were performed to find safe and potential inhibitors of SARS-CoV-2 Mpro. We have identified ZINC02123811 (1-(3-(2,5,9-trimethyl-7-oxo-3-phenyl-7H-furo[3,2-g]chromen-6-yl)propanoyl)piperidine-4-carboxamide), a natural compound bearing appreciable affinity, efficiency, and specificity towards the binding pocket of SARS-CoV-2 Mpro. The identified compound showed a set of drug-like properties and preferentially binds to the active site of SARS-CoV-2 Mpro. All-atom molecular dynamics (MD) simulations were performed to evaluate the conformational dynamics, stability and interaction mechanism of Mpro with ZINC02123811. MD simulation results indicated that Mpro with ZINC02123811 forms a stable complex throughout the trajectory of 100 ns. These findings suggest that ZINC02123811 may be further exploited as a promising scaffold for the development of potential inhibitors of SARS-CoV-2 Mpro to address COVID-19.
| S-EPMC7839507 | biostudies-literature