In silico approach for the development of novel antiviral compounds based on SARS-COV-2 protease inhibition.
Ontology highlight
ABSTRACT: Supplementary information
The online version contains supplementary material available at 10.1007/s11696-022-02170-8.
SUBMITTER: Nickcovic VP
PROVIDER: S-EPMC8977062 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
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: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.
| S-EPMC9398018 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic by the World Health Organization, and the situation worsens daily, associated with acute increases in case fatality rates. The main protease (Mpro) enzyme produced by SARS-CoV-2 was recently demonstrated to be responsible for not only viral reproduction but also impeding host immune responses. The element selenium (Se) plays a vital role in immune functions, both directly and indirectly. Thus, we hypothesised that Se-containing heterocyclic compounds might curb the activity of SARS-CoV-2 Mpro. We performed a molecular docking analysis and found that several of the selected selenocompounds showed potential binding affinities for SARS-CoV-2 Mpro, especially ethaselen (49), which exhibited a docking score of -6.7 kcal/mol compared with the -6.5 kcal/mol score for GC376 (positive control). Drug-likeness calculations suggested that these compounds are biologically active and possess the characteristics of ideal drug candidates. Based on the binding affinity and drug-likeness results, we selected the 16 most effective selenocompounds as potential anti-COVID-19 drug candidates. We also validated the structural integrity and stability of the drug candidate through molecular dynamics simulation. Using further in vitro and in vivo experiments, we believe that the targeted compound identified in this study (ethaselen) could pave the way for the development of prospective drugs to combat SARS-CoV-2 infections and trigger specific host immune responses.
| S-EPMC7929402 | biostudies-literature
Project description:The current scenario across the globe shows unprecedented healthcare and an economic crisis due to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Recently, the World Health Organization (WHO) has declared a pandemic stage worldwide because of the high mortality and morbidity rate caused by novel infection disease. There have been several clinical trials and identification underway to find a treatment of this novel virus. For the treatment of severe infection involves the blocking of the replication of its CoV-2 protein. Hydroxychloroquine and remdesivir has been used on an emergency basis for its treatment. The uncontrolled infection and increasing death rate underline the emergence to develop the antiviral drug. In our study, the blind docking of various classes of compounds including control antiviral drugs (abacavir, acyclovir, quinoline, hydroxyquinoline), antimicrobial drugs (levofloxacin, amoxicillin, cloxacin, ofloxacin), natural compounds (lycorine, saikosaponins, myricetin, amentaflavone), herbal compounds (silymarin, palmatine, curcumin, eugenin) available in Indian Ayurveda was done. Besides, we have also performed the blind docking of various ionic liquids (ILs) such as pyrrolidinium, piperidinium, pyridinium, imidazolium based ILs against CoV-2 protease as they have recently emerged as a potential antimicrobial agent. Further, the pharmacokinetic properties and cytotoxicity of the compounds were determined computationally. The docking results showed successful binding to the active site or near a crucial site. The present computational approach was found helpful to predict the best possible inhibitor of protease and may result in an effective therapeutic agent against COVID-19.
| S-EPMC7832122 | biostudies-literature
Project description:The world has witnessed of many pandemic waves of SARS-CoV-2. However, the incidence of SARS-CoV-2 infection has now declined but the novel variant and responsible cases has been observed globally. Most of the world population has received the vaccinations, but the immune response against COVID-19 is not long-lasting, which may cause new outbreaks. A highly efficient pharmaceutical molecule is desperately needed in these circumstances. In the present study, a potent natural compound that could inhibit the 3CL protease protein of SARS-CoV-2 was found with computationally intensive search. This research approach is based on physics-based principles and a machine-learning approach. Deep learning design was applied to the library of natural compounds to rank the potential candidates. This procedure screened 32,484 compounds, and the top five hits based on estimated pIC50 were selected for molecular docking and modeling. This work identified two hit compounds, CMP4 and CMP2, which exhibited strong interaction with the 3CL protease using molecular docking and simulation. These two compounds demonstrated potential interaction with the catalytic residues His41 and Cys154 of the 3CL protease. Their calculated binding free energies to MMGBSA were compared to those of the native 3CL protease inhibitor. Using steered molecular dynamics, the dissociation strength of these complexes was sequentially determined. In conclusion, CMP4 demonstrated strong comparative performance with native inhibitors and was identified as a promising hit candidate. This compound can be applied in-vitro experiment for the validation of its inhibitory activity. Additionally, these methods can be used to identify new binding sites on the enzyme and to design new compounds that target these sites.
| S-EPMC10104361 | biostudies-literature
Project description:Over 10 years have passed since the deadly human coronavirus that causes severe acute respiratory syndrome (SARS-CoV) emerged from the Guangdong Province of China. Despite the fact that the SARS-CoV pandemic infected over 8500 individuals, claimed over 800 lives and cost billions of dollars in economic loss worldwide, there still are no clinically approved antiviral drugs, vaccines or monoclonal antibody therapies to treat SARS-CoV infections. The recent emergence of the deadly human coronavirus that causes Middle East respiratory syndrome (MERS-CoV) is a sobering reminder that new and deadly coronaviruses can emerge at any time with the potential to become pandemics. Therefore, the continued development of therapeutic and prophylactic countermeasures to potentially deadly coronaviruses is warranted. The coronaviral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), are attractive antiviral drug targets because they are essential for coronaviral replication. Although the primary function of PLpro and 3CLpro are to process the viral polyprotein in a coordinated manner, PLpro has the additional function of stripping ubiquitin and ISG15 from host-cell proteins to aid coronaviruses in their evasion of the host innate immune responses. Therefore, targeting PLpro with antiviral drugs may have an advantage in not only inhibiting viral replication but also inhibiting the dysregulation of signaling cascades in infected cells that may lead to cell death in surrounding, uninfected cells. This review provides an up-to-date discussion on the SARS-CoV papain-like protease including a brief overview of the SARS-CoV genome and replication followed by a more in-depth discussion on the structure and catalytic mechanism of SARS-CoV PLpro, the multiple cellular functions of SARS-CoV PLpro, the inhibition of SARS-CoV PLpro by small molecule inhibitors, and the prospect of inhibiting papain-like protease from other coronaviruses. This paper forms part of a series of invited articles in Antiviral Research on "From SARS to MERS: 10years of research on highly pathogenic human coronaviruses."
| S-EPMC5896749 | biostudies-literature
Project description:Since there is no general agreement on drug treatment of SARS-CoV-2, the search for a new drug capable of treating COVID-19 is of utmost priority. This study aims to dereplicate the chemical compounds of the methanol extract of Salvia officinalis and Artemisia dracunculus, and assay the inhibitory effect of these compounds as well as the previously dereplicated components of Zingiber officinale against SARS-CoV-2 in an in-silico study. A molecular networking (MN) technique was applied to find the chemical constituents of the extracts. Docking analysis was also used to find the binding affinity of dereplicated components from S. officinalis, A. dracunculus, and Z. officinale to COV-2-SP and Mpro. 57 compounds were dereplicated from the MeOH extracts of S. officinalis and A. dracunculus which include the class of polyphenols, flavonoids, coumarins, phenylpropanoids, anthocyanins, and dihydrochalcones. Molecular docking analysis indicated a high affinity of about 27 compounds from three mentioned plants against studied targets. kaempferol 3-O-rutinoside, neodiosmin, and querciturone with docking score values of -10.575, -10.208, and - 9.904 Kcal/mol and ki values of 0.016606, 0.030921, and 0.051749, respectively were found to have the highest affinities against COV-2-SP. 2-phenylethyl beta-primeveroside, curcumin PE, and kaempferol 3-O-rutinoside also indicated the highest affinity against Mpro with docking scores of -10.34, -10.126 and - 9.705 and ki values of 0.024726, 0.035529, and 0.072494, respectively. MN can be successfully used for the dereplication of metabolites from plant extracts. In addition, the in-silico binding energies introduced several inhibitors from Z. officinale, S. officinalis, and A. dracunculus for the treatment of SARS-CoV-2 disease.Supplementary informationThe online version contains supplementary material available at 10.1007/s11756-021-00881-z.
| S-EPMC8456686 | biostudies-literature
Project description:ObjectivesOver the years, Azadirachta indica, Mangifera indica, and Moringa oleifera have been shown to possess some antiviral characteristics. This study applies molecular docking techniques to assess inhibitory effects of some bioactive compounds from the plants mentioned above against the main protease (Mpro), a key protein involved in SARS-CoV-2 replication. Furthermore, adsorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles for screened compounds were predicted in silico.MethodsThe crystal structure of Mpro was retrieved from the Protein Data Bank, while the plant bioactive compounds were retrieved from Pubchem. Drug-likeness of the selected compounds and a control drug (hydroxychloroquine) were assessed, and the compounds that satisfied the drug-likeness rule were docked against Mpro. The docked complexes were analyzed using LigPlot and the protein-ligand profiler server. The top five compound hits were subjected to ADMET screening using the ADMETSar server.ResultsA total of 17 out of 22 screened compounds passed Lipinski's assessment. Additionally, the most active compounds from the investigated plants exhibited relative inhibitory potentials against Mpro compared with hydroxychloroquine, which alludes to their possible involvement in inhibiting the SARS-CoV-2 main protease replication process.ConclusionsIn our study, most of the active phytocomponents of the investigated plants exhibited relative inhibitory potentials against Mpro of SARS-CoV-2 and preferred pharmacological features when compared with hydroxychloroquine. These findings indicate these compounds are potentially antiviral candidates against SARS-CoV-2.
| S-EPMC7787523 | biostudies-literature
Project description:Background and aimCoronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now become the world pandemic. There is a race to develop suitable drugs and vaccines for the disease. The anti-HIV protease drugs are currently repurposed for the potential treatment of COVID-19. The drugs were primarily screened against the SARS-CoV-2 main protease. With an urgent need for safe and effective drugs to treat the virus, we have explored natural products isolated from edible and medicinal mushrooms that have been reported to possess anti-HIV protease.Experimental proceduresWe have examined 36 compounds for their potential to be SARS-CoV-2 main protease inhibitors using molecular docking study. Moreover, drug-likeness properties including absorption, distribution, metabolism, excretion and toxicity were evaluated by in silico ADMET analysis.ResultsOur AutoDock study showed that 25 of 36 candidate compounds have the potential to inhibit the main viral protease based on their binding affinity against the enzyme's active site when compared to the standard drugs. Interestingly, ADMET analysis and toxicity prediction revealed that 6 out of 25 compounds are the best drug-like property candidates, including colossolactone VIII, colossolactone E, colossolactone G, ergosterol, heliantriol F and velutin.ConclusionOur study highlights the potential of existing mushroom-derived natural compounds for further investigation and possibly can be used to fight against SARS-CoV-2 infection.Taxonomy classification by eviseDisease, Infectious Disease, Respiratory System Disease, Covid-19, Traditional Medicine, Traditional Herbal Medicine, Phamaceutical Analysis.
| S-EPMC7836338 | biostudies-literature
Project description:The biggest challenge in medical management and control of the COVID-19 pandemic is the nonavailability of the treatment molecules. While vaccines and other biotherapeutic products for managing COVID-19 have reached the market, a small-molecule cure is yet to be developed. This is relevant because the cost of production, storage, and ease of distribution of a small-molecule drug are significantly more favorable than those of biologics. In this paper, we present a multicompound approach, where two drug molecules are administered concurrently to offer an effective therapy for COVID-19. The co-action of the two compounds, each derived from natural origins, has been demonstrated against the 3CL protease, already recognized as a potential drug target for inhibiting SARS-CoV-2. The pair of compounds pursued in this study are flavonoid and naphthalene scaffold. Individually, they offer ∼30 to 35% inhibition at 10 μM. Comprehensive docking and molecular dynamics simulations elucidate that these compounds exhibit excellent binding in the process, which however quickly deteriorates, and the ligand is separated from the binding site. This suggests that while the ligands initially bind with the protease, they are unable to maintain it for an extended period. However, the simulation showed that a simultaneous docked complex of both the compounds together with the protein boosts the stronger binding for a sufficient time. The enzyme assay exhibited 97 and 85% inhibition activity when both compounds were used together at 100 and 50 μM, respectively. Later, a multiconcentration assay was used to determine the coinhibitory activity, and it was observed that the compounds have ∼20 to 30% inhibition activity even at lower concentrations of 0.5 and 1 μM. Surface plasmon resonance was used to measure the binding of the compounds, and when used together, the compounds had a 10-fold greater binding affinity. Thus, the results demonstrate a synergistic mechanism between the two compounds that enhances the inhibition activity against SARS-CoV-2 3CL protease.
| S-EPMC8565457 | biostudies-literature