In-silico screening of naturally derived phytochemicals against SARS-CoV Main protease.
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ABSTRACT:
SUBMITTER: Mostafa I
PROVIDER: S-EPMC8638226 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) pandemic has become a global challenge based on its replication within the host cells that relies on non-structural proteins, protease (Mpro). Flavonoids, an important class of naturally occurring compounds with medicinal importance, are frequently available within fruits and vegetables. Herein, we report the in silico studies on naturally occurring flavonoids consisting of molecular docking studies and evaluation of theoretical kinetics. In this study, we prepared a library of nine different classes of naturally occurring flavonoids and screened them on Autodock and Autodockvina. The pharmacokinetic properties of most promising compounds have been predicted through ADMET SAR, inhibition constants, ligand efficiency and ligand fit quality have been worked out theoretically. The results revealed that naturally occurring flavonoids could fit well in the receptor's catalytic pocket, interact with essential amino acid residues and could be useful for future drug candidates through in vitro and in vivo studies. Moreover, MD simulation studies were conducted for two most promising flavonoids and the protein-ligand complexes were found quite stable. The selected natural flavonoids are free from any toxic effects and can be consumed as a preventive measure against SARS CoV-2.
| S-EPMC8502681 | biostudies-literature
Project description:Phyllanthus amarus, also known as Bhui Korma in India, is well known for its medicinal properties and is used to treat several diseases worldwide. This study aims to identify phytochemicals from P. amarus and assess their anti-viral activity through in silico methods against the main protease (3CLPro/MPro) enzyme of the novel coronavirus. 190 compounds were obtained from literature and docked against 3CLPro and 16 compounds showed higher binding affinity with 3CLPro with their values lying between -8.9 kcal/mol to -9.6 kcal/mol. The top two compounds, Myricitrin (CID: 5352000) and Quercetin-3-O-glucuronide (CID: 12004528) gave high binding affinity values of -9.6 kcal/mol and -9.4 kcal/mol respectively and also display favourable binding interactions with the 3CLPro. Both the compounds were further subjected to molecular dynamics simulation and MM-PBSA based binding free energy calculations. ADMET and drug-likeness properties were studied to assess the pharmacokinetic properties of the compounds. Favourable pharmacokinetic results reinforced the applicability of the compounds assessed. Along with continuous studies being carried out with chemical compounds, research needs to expand into all areas, including the use of natural compounds as drug compounds. The identified hits from this study can be taken further for in vitro and in vivo studies to examine their efficacy against COVID-19. Graphical abstract Image 1
| S-EPMC8364217 | biostudies-literature
Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that causes COVID-19 disease is still a major public health concern around the world. The main protease encoded by SARS-CoV-2 is a promising target for COVID-19 therapeutic development since it plays a crucial role in the virus’s life cycle. Repurposing known bioactive molecules is an effective strategy to fast-track the delivery of hits and leads in drug discovery. In this regard, this study assesses in-silico, 17 acridone-based alkaloids for their activity against SARS-CoV-2 main protease. The quantum chemical computations imply that the acridone alkaloids will interact better in the active sites of the enzymes due to their low energy gap. They also have good oral bioavailability as rationalized by “no rule of five violation" and favorable pharmacokinetics parameters. From the docking results, many of the alkaloids displayed a higher binding affinity than nirmatrelvir, an authorised protease inhibitor. Compound 3 (5-hydroxynoracronycine alcohol), with the better binding affinities (6W63, − 7.094 kcal/mol; 5R82, − 5.839 kcal/mol) and unique structural features is a viable candidate that could be investigated further for development of a novel target specific chemotherapeutic agent to stop SARS-CoV-2 invasion.
| S-EPMC9465131 | biostudies-literature
Project description:The COVID-19 pandemic has been a public health emergency, with deadly forms constantly emerging around the world, highlighting the dire need for highly effective antiviral therapeutics. Peptide therapeutics show significant potential for this viral disease due to their efficiency, safety, and specificity. Here, two thousand seven hundred eight antibacterial peptides were screened computationally targeting the Main protease (Mpro) of SARS CoV-2. Six top-ranked peptides according to their binding scores, binding pose were investigated by molecular dynamics to explore the interaction and binding behavior of peptide-Mpro complexes. The structural and energetic characteristics of Mpro-DRAMP01760 and Mpro-DRAMP01808 complexes fluctuated less during a 250 ns MD simulation. In addition, three peptides (DRAMP01760, DRAMP01808, and DRAMP01342) bind strongly to Mpro protein, according to the free energy landscape and principal component analysis. Peptide helicity and secondary structure analysis are in agreement with our findings. Interaction analysis of protein-peptide complexes demonstrated that Mpro's residue CYS145, HIS41, PRO168, GLU166, GLN189, ASN142, MET49, and THR26 play significant contributions in peptide-protein attachment. Binding free energy analysis (MM-PBSA) demonstrated the energy profile of interacting residues of Mpro in peptide-Mpro complexes. To summarize, the peptides DRAMP01808 and DRAMP01760 may be highly Mpro specific, resulting disruption in a viral replication and transcription. The results of this research are expected to assist future research toward the development of antiviral peptide-based therapeutics for Covid-19 treatment.
| S-EPMC9877796 | biostudies-literature
Project description:The SARS-Cov-2 virus, which is evolving continuously and causing adverse effects throughout the world, needs an effective drug molecule for its treatment. There are several receptors of SARS Cov-2 which are targeted for its inhibition by many lead molecules both in-vitro and in-vivo. Papain like Protease (PLpro) is one of the two SARS-Cov-2 proteases that can be used as a drug target for SARS Cov-2. It is a coronavirus enzyme that plays a role in the cleavage and maturation of viral polyproteins, assembly of the replicase-transcriptase complex and disruption of host responses. PLpro has also been linked to the cleavage of proteinaceous post translational modifications on host proteins as a means of evading antiviral immune responses. Structure-based drug discovery can be one of the effective methods to screen for various molecules against the target receptors. In this study, PLpro of SARS CoV-2 was chosen as the target for docking. Forty phytochemicals from various plant sources and four synthetic drugs have been screened for their inhibitory potential against PLpro using AutoDock Vina. Phytochemicals such as Tinosponone, Rhoifolin, Rosmanol, Berberin, Nimbin and two other existing drugs Elbasvir and Declatasvir showed higher inhibitory potential in terms of higher binding affinities. ADME and toxicity analysis were also performed to predict the pharmacokinetics and drug likeliness properties. It was concluded from the study that Tinosponone possesss potential inhibitor property of papain-like proteases (PLpro) of SARS CoV-2. Tinosponone from the plant Tinospora cordifolia had a binding affinity of - 9.3 kcal/mol and obeyed the Lipinski rules, making it an effective lead molecule for treating SARS CoV-2. Molecular Dynamics simulation of Tinosponone with PLpro has proved the stability and validity of the binding with RMSD value in range of 0.2 nm when it was run for 50 ns using GROMACS. Therefore, Tinosponone could be considered as a potential inhibitor of PLpro of SARS CoV-2.
| S-EPMC9734692 | biostudies-literature
Project description:Novel Coronavirus or SARS-CoV-2 outbreak has developed a pandemic condition all over the world. The virus is highly infectious and spreads by human to human local transmission mode. Till date, there is no vaccination or drugs been approved for the treatment by the World Health Organisation. Henceforth, the discovery of the potential drugs is an urgent and utmost requirement for the medical fraternity. Since, the side effects of plant-derived compounds will be lower compared to synthetic/chemical drugs. The Main protease (3CLpro or NSP5) and endoribonuclease (NSP15) proteins are necessity for viral replication and its survival in the host cell. In the present study, in-silico approach of drug development was used to search for potential antiviral plant-derived compounds as inhibitors against SARS-CoV-2 replication proteins. Eight plant-derived compounds of which the antiviral activity was known and available, and two reported drugs against SARS-CoV-2 selected for the molecular docking analysis. The docking results suggested that bisdemethoxycurcumin, demethoxycurcumin, scutellarin, quercetin and myricetin showed least binding energy, i.e., greater than -6.5 Kcal/mol against 3CLpro and endoribonuclease of SARS-CoV-2. Further studies of ADME-Tox and bioavailability of drugs were also performed that exhibited efficient parameters of drug likeness. Molecular dynamics simulation calculations were performed for the most negative binding affinity of the compound to evaluate the dynamic behavior,and stability of protein-ligand complex. Our findings suggest that these compounds could be potential inhibitors of SARS-CoV-2 main protease and endoribonuclease. However, further in-vitro and pre-clinical experiments would validate the potential inhibitors of SARS-CoV-2 proteins.
| S-EPMC7544953 | biostudies-literature
Project description:Given the COVID-19 pandemic, currently, there are many drugs in clinical trials against this virus. Among the excellent drug targets of SARS-CoV-2 are its proteases (Nsp3 and Nsp5) that plays vital role in polyprotein processing giving rise to functional nonstructural proteins, essential for viral replication and survival. Nsp5 (also known as Mpro) hydrolyzes replicase polyprotein (1ab) at eleven different sites. For targeting Mpro, we have employed drug repurposing approach to identify potential inhibitors of SARS-CoV-2 in a shorter time span. Screening of approved drugs through docking reveals Hyaluronic acid and Acarbose among the top hits which are showing strong interactions with catalytic site residues of Mpro. We have also performed docking of drugs Lopinavir, Ribavirin, and Azithromycin on SARS-CoV-2 Mpro. Further, binding of these compounds (Hyaluronic acid, Acarbose, and Lopinavir) is validated by extensive molecular dynamics simulation of 500 ns where these drugs show stable binding with Mpro. We believe that the high-affinity binding of these compounds will help in designing novel strategies for structure-based drug discovery against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
| S-EPMC7678354 | biostudies-literature
Project description:The main protease of SARS-CoV-2 is one of the important targets to design and develop antiviral drugs. In this study, we have selected 40 antiviral phytochemicals to find out the best candidates which can act as potent inhibitors against the main protease. Molecular docking is performed using AutoDock Vina and GOLD suite to determine the binding affinities and interactions between the phytochemicals and the main protease. The selected candidates strongly interact with the key Cys145 and His41 residues. To validate the docking interactions, 100?ns molecular dynamics (MD) simulations on the five top-ranked inhibitors including hypericin, cyanidin 3-glucoside, baicalin, glabridin, and ?-ketoamide-11r are performed. Principal component analysis (PCA) on the MD simulation discloses that baicalin, cyanidin 3-glucoside, and ?-ketoamide-11r have structural similarity with the apo-form of the main protease. These findings are also strongly supported by root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (Rg), and solvent accessible surface area (SASA) investigations. PCA is also used to find out the quantitative structure-activity relationship (QSAR) for pattern recognition of the best ligands. Multiple linear regression (MLR) of QSAR reveals the R2 value of 0.842 for the training set and 0.753 for the test set. Our proposed MLR model can predict the favorable binding energy compared with the binding energy detected from molecular docking. ADMET analysis demonstrates that these candidates appear to be safer inhibitors. Our comprehensive computational and statistical analysis show that these selected phytochemicals can be used as potential inhibitors against the SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
| S-EPMC7232885 | biostudies-literature
Project description:Euphorbia hirta L. is a medicinal plant widely used in the Philippines and across tropical Asia against various diseases, including respiratory disorders. In this study, the phytochemical components of E. hirta were investigated in silico for their potential to inhibit the severe acute respiratory syndrome-coronavirus-2 main protease (SARS-CoV-2 Mpro), a coronavirus disease 2019 (COVID-19) drug target that plays a critical role in the infection process of SARS-CoV-2. Phytochemical mining in tandem with virtual screening (PM-VS) was the strategy implemented in this study, which allows efficient preliminary in silico assessment of the COVID-19 therapeutic potential of the reported phytochemicals from the plant. The main rationale for considering E. hirta in the investigation was its reported efficacy against respiratory disorders. It is very promising to investigate the phytochemicals of E. hirta for their potential efficacy against diseases, such as COVID-19, that also target the respiratory system. A total of 298 E. hirta phytochemicals were comprehensively collected from the scientific literature. One hundred seventy of these phytochemicals were computed through molecular docking and were shown to have comparable or better binding properties (promising inhibitors) toward SARS-CoV-2 Mpro than known in vitro inhibitors. In connection to our previous work considering different medicinal plants, antiviral compounds were also rediscovered from the phytochemical composition of E. hirta. This finding provides additional basis for the potential of the plant (or its phytochemicals) as a COVID-19 therapeutic directly targeting drug targets such as SARS-CoV-2 Mpro and/or addressing respiratory-system-related symptoms. The study also highlights the utility of PM-VS, which can be efficiently implemented in the preliminary steps of drug discovery and development.
| S-EPMC8855059 | biostudies-literature
Project description:At the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission was human-to-human contact and hence resulted in a rapid surge across the globe where more than 24 million people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy, and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger's GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir, and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.
| S-EPMC7521772 | biostudies-literature