scholarly journals In Silico Evaluation of Different Flavonoids from Medicinal Plants for Their Potency against SARS-CoV-2

Biologics ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 416-434
Author(s):  
H. R. Abd El-Mageed ◽  
Doaa A. Abdelrheem ◽  
Md. Oliullah Rafi ◽  
Md. Takim Sarker ◽  
Khattab Al-Khafaji ◽  
...  
Keyword(s):  
Medicinal Plants ◽  
Binding Affinity ◽  
Active Sites ◽  
Protein Complexes ◽  
Biological Effects ◽  
Strong Stability ◽  
Md Simulations ◽  
Antiviral Drugs ◽  
Spike Protein ◽  
Global Threat

The ongoing pandemic situation of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global threat to both the world economy and public health. Therefore, there is an urgent need to discover effective vaccines or drugs to fight against this virus. The flavonoids and their medicinal plant sources have already exhibited various biological effects, including antiviral, anti-inflammatory, antioxidant, etc. This study was designed to evaluate different flavonoids from medicinal plants as potential inhibitors against the spike protein (Sp) and main protease (Mpro) of SARS-CoV-2 using various computational approaches such as molecular docking, molecular dynamics. The binding affinity and inhibitory effects of all studied flavonoids were discussed and compared with some antiviral drugs that are currently being used in COVID-19 treatment namely favipiravir, lopinavir, and hydroxychloroquine, respectively. Among all studies flavonoids and proposed antiviral drugs, luteolin and mundulinol exhibited the highest binding affinity toward Mpro and Sp. Drug-likeness and ADMET studies revealed that the chosen flavonoids are safe and non-toxic. One hundred ns-MD simulations were implemented for luteolin-Mpro, mundulinol-Mpro, luteolin-Sp, and mundulinol-Sp complexes and the results revealed strong stability of these flavonoid-protein complexes. Furthermore, MM/PBSA confirms the stability of luteolin and mundulinol interactions within the active sites of this protein. In conclusion, our findings reveal that the promising activity of luteolin and mundulinol as inhibitors against COVID-19 via inhibiting the spike protein and major protease of SARS CoV-2, and we urge further research to achieve the clinical significance of our proposed molecular-based efficacy.

scholarly journals In silico and in vitro Demonstration of Homoharrintonine Antagonism of RBD-ACE2 Binding and its Anti-inflammatory and anti-thrombogenic Properties in a 3D human vascular lung model

2021 ◽  
Author(s):  
Shalini Saxena ◽  
Kranti Meher ◽  
Madhuri Rotella ◽  
Subhramanyam Vangala ◽  
Satish Chandran ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Active Sites ◽  
Cell Model ◽  
Antiviral Drugs ◽  
Lung Model ◽  
Host Cells ◽  
Spike Protein ◽  
Prevention And Treatment ◽  
Anti Inflammatory

Since 2019 the world has seen severe onslaught of SARS-CoV-2 viral pandemic. There is an urgent need for drugs that can be used to either prevent or treat the potentially fatal disease COVD-19. To this end, we screened FDA approved antiviral drugs which could be repurposed for COVID-19 through molecular docking approach in the various active sites of receptor binding domain (RBD). The RBD domain of SARS-CoV-2 spike protein is a promising drug target due to its pivotal role in viral-host attachment. Specifically, we focussed on identifying antiviral drugs which could a) block the entry of virus into host cells, b) demonstrate anti-inflammatory and/or anti-thrombogenic properties. Drugs which poses both properties could be useful for prevention and treatment of the disease. While we prioritized a few antiviral drugs based on molecular docking, corroboration with in vitro studies including a new 3D human vascular lung model strongly supported the potential of Homoharringtonine, a drug approved for chronic myeloid leukaemia to be repurposed for COVID-19. This natural product drug not only antagonized the biding of SARS-CoV-2 spike protein RBD binding to human angiotensin receptor 2 (ACE-2) protein but also demonstrated for the first time anti-thrombogenic and anti-leukocyte adhesive properties in a human cell model system. Overall, this work provides an important lead for development of rapid treatment of COVID-19 and also establishes a screening paradigm using molecular modelling and 3D human vascular lung model of disease to identify drugs with multiple desirable properties for prevention and treatment of COVID-19.

scholarly journals In silico Investigation on the Inhibiting Role of Nicotine/Caffeine by Blocking the S Protein of SARS-CoV-2 Versus ACE2 Receptor

2020 ◽  
Vol 8 (10) ◽  
pp. 1600 ◽  
Author(s):  
Saeedeh Mohammadi ◽  
Mohammad Heidarizadeh ◽  
Mehrnaz Entesari ◽  
Ayoub Esmailpour ◽  
Mohammad Esmailpour ◽  
...  
Keyword(s):  
In Silico ◽  
Active Sites ◽  
Md Simulations ◽  
Antiviral Drugs ◽  
Molar Ratio ◽  
Converting Enzyme ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Human Receptor

In this paper, we studied the in silico interaction of angiotensin-converting enzyme 2 (ACE2) human receptor with two bioactive compounds, i.e., nicotine and caffeine, via molecular dynamic (MD) simulations. The simulations reveal the efficient blocking of ACE2 by caffeine and nicotine in the exposure to the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have selected the two most important active sites of ACE2-S protein, i.e., 6LZG and 6VW1, which are critically responsible in the interaction of S protein to the receptor and thus, we investigated their interaction with nicotine and caffeine through MD simulations. Caffeine and nicotine are interesting structures for interactions because of their similar structure to the candidate antiviral drugs. Our results reveal that caffeine or nicotine in a specific molar ratio to 6LZG shows a very strong interaction and indicate that caffeine is more efficient in the interaction with 6LZG and further blocking of this site against S protein binding. Further, we investigated the interaction of ACE2 receptor- S protein with nicotine or caffeine when mixed with candidate or approved antiviral drugs for SARS-CoV-2 therapy. Our MD simulations suggest that the combination of caffeine with ribavirin shows a stronger interaction with 6VW1, while in case of favipiravir+nicotine, 6LZG shows potent efficacy of these interaction, proposing the potent efficacy of these combinations for blocking ACE2 receptor against SARS-CoV-2.

Molecular Docking and Dynamics Simulation of Natural Phenolic Compounds with GSK-3β: A Putative Target to Combat Mortality in Patients with COVID-19

2021 ◽  
Vol 14 ◽  
Author(s):  
Zahra Khamverdi ◽  
Zeinab Mohamadi ◽  
Amir Taherkhani
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
Phenolic Compounds ◽  
Binding Affinity ◽  
Active Sites ◽  
Interaction Network ◽  
Md Simulations ◽  
Dynamics Simulation ◽  
Discovery Studio ◽  
Gsk 3Β

Objective: In this study, molecular docking analysis was performed to evaluate the binding affinity of 52 plant-based phenolics with the GSK-3β active sites. Moreover, Molecular Dynamics (MD) simulation was conducted to investigate the stability of interactions between the topranked phenolics and residues within the GSK-3β active sites. Methods: Molecular docking and MD simulations were performed using AutoDock and Discovery Studio Client software, respectively. Thereafter, pharmacokinetic and toxicological properties of top inhibitors were predicted using bioinformatics web tools. This study aimed to identify the most effective amino acids involved in the inhibition of GSK-3β based on the most stabilizing interactions between the residues and compounds, and also by considering the degree centrality in the ligand-amino acid interaction network for GSK-3β. Results: It was observed that procyanidin and amentoflavone could bind to the GSK-3β active sites at the picomolar (pM) scale as well as the binding affinity of ∆G binding < -13 kcal/mol, while the inhibition constant for theaflavin 3’-gallate, procyanidin B4, and rutin was calculated at the nanomolar (nM) scale, suggesting that these phenolic compounds can be considered as potential effective GSK-3β inhibitors. Furthermore, Val70, Ala83, Val135, and Tyr134 were found to be the most important amino acids involved in the inhibition of GSK-3β. Conclusion: The results of the current study may be useful in the prevention of several human disorders, including COVID-19, cancers, Alzheimer’s disease, diabetes mellitus, and cardiovascular diseases. However, wet-lab experiments need to be performed in the future.

Discovery of Some Antiviral Natural products to fight against Novel Corona Virus (SARS-CoV-2) using Insilico approach

2020 ◽  
Vol 23 ◽  
Author(s):  
Ashish Shah ◽  
Vaishali Patel ◽  
Bhumika Parmar
Keyword(s):  
Binding Affinity ◽  
Protein S ◽  
Docking Studies ◽  
Spike Protein ◽  
Enveloped Viruses ◽  
Bioactivity Prediction ◽  
Corona Virus ◽  
Main Protease ◽  
Antiviral Activities ◽  
Deadly Disease

Background: Novel Corona virus is a type of enveloped viruses with a single stranded RNA enclosing helical nucleocapsid. The envelope consists of spikes on the surface which are made up of proteins through which virus enters into human cells. Until now there is no specific drug or vaccine available to treat COVID-19 infection. In this scenario, reposting of drug or active molecules may provide rapid solution to fight against this deadly disease. Objective: We had selected 30 phytoconstituents from the different plants which are reported for antiviral activities against corona virus (CoVs) and performed insilico screening to find out phytoconstituents which have potency to inhibit specific target of novel corona virus. Methods: We had perform molecular docking studies on three different proteins of novel corona virus namely COVID-19 main protease (3CL pro), papain-like protease (PL pro) and spike protein (S) attached to ACE2 binding domain. The screening of the phytoconstituents on the basis of binding affinity compared to standard drugs. The validations of screened compounds were done using ADMET and bioactivity prediction. Results: We had screened five compounds biscoclaurine, norreticuline, amentoflavone, licoricidin and myricetin using insilico approach. All compounds found safe in insilico toxicity studies. Bioactivity prediction reviles that these all compounds may act through protease or enzyme inhibition. Results of compound biscoclaurine norreticuline were more interesting as this biscoclaurine had higher binding affinity for the target 3CLpro and PLpro targets and norreticuline had higher binding affinity for the target PLpro and Spike protein. Conclusion: Our study concludes that these compounds could be further explored rapidly as it may have potential to fight against COVID-19.

scholarly journals Deciphering the Interactions of Bioactive Compounds in Selected Traditional Medicinal Plants against Alzheimer’s Diseases via Pharmacophore Modeling, Auto-QSAR, and Molecular Docking Approaches

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1996
Author(s):  
 Oluwafemi Adeleke Ojo ◽  
Adebola Busola Ojo ◽  
Charles Okolie ◽  
Mary-Ann Chinyere Nwakama ◽  
Matthew Iyobhebhe ◽  
...  
Keyword(s):  
Medicinal Plants ◽  
Receiver Operating Characteristic ◽  
Binding Affinity ◽  
Operating Characteristic ◽  
Characteristic Curve ◽  
Screening Method ◽  
Pharmacophore Modeling ◽  
Structure Identification ◽  
Mao Activity ◽  
Receiver Operating

Neurodegenerative diseases, for example Alzheimer’s, are perceived as driven by hereditary, cellular, and multifaceted biochemical actions. Numerous plant products, for example flavonoids, are documented in studies for having the ability to pass the blood-brain barrier and moderate the development of such illnesses. Computer-aided drug design (CADD) has achieved importance in the drug discovery world; innovative developments in the aspects of structure identification and characterization, bio-computational science, and molecular biology have added to the preparation of new medications towards these ailments. In this study we evaluated nine flavonoid compounds identified from three medicinal plants, namely T. diversifolia, B. sapida, and I. gabonensis for their inhibitory role on acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoamine oxidase (MAO) activity, using pharmacophore modeling, auto-QSAR prediction, and molecular studies, in comparison with standard drugs. The results indicated that the pharmacophore models produced from structures of AChE, BChE and MAO could identify the active compounds, with a recuperation rate of the actives found near 100% in the complete ranked decoy database. Moreso, the robustness of the virtual screening method was accessed by well-established methods including enrichment factor (EF), receiver operating characteristic curve (ROC), Boltzmann-enhanced discrimination of receiver operating characteristic (BEDROC), and area under accumulation curve (AUAC). Most notably, the compounds’ pIC50 values were predicted by a machine learning-based model generated by the AutoQSAR algorithm. The generated model was validated to affirm its predictive model. The best models achieved for AChE, BChE and MAO were models kpls_radial_17 (R2 = 0.86 and Q2 = 0.73), pls_38 (R2 = 0.77 and Q2 = 0.72), kpls_desc_44 (R2 = 0.81 and Q2 = 0.81) and these externally validated models were utilized to predict the bioactivities of the lead compounds. The binding affinity results of the ligands against the three selected targets revealed that luteolin displayed the highest affinity score of −9.60 kcal/mol, closely followed by apigenin and ellagic acid with docking scores of −9.60 and −9.53 kcal/mol, respectively. The least binding affinity was attained by gallic acid (−6.30 kcal/mol). The docking scores of our standards were −10.40 and −7.93 kcal/mol for donepezil and galanthamine, respectively. The toxicity prediction revealed that none of the flavonoids presented toxicity and they all had good absorption parameters for the analyzed targets. Hence, these compounds can be considered as likely leads for drug improvement against the same.

scholarly journals Insight into Inhibitor Binding in the Eukaryotic Proteasome: Computations of the 20S CP

2018 ◽  
Vol 19 (12) ◽  
pp. 3858
Author(s):  
Milan Hodošček ◽  
Nadia Elghobashi-Meinhardt
Keyword(s):  
Electrostatic Interactions ◽  
Active Sites ◽  
Sampling Period ◽  
Md Simulations ◽  
Structural Features ◽  
Relaxation Dynamics ◽  
Inhibitor Binding ◽  
Computational Analyses ◽  
Insight Into ◽  
Proteolytic Chamber

A combination of molecular dynamics (MD) simulations and computational analyses uncovers structural features that may influence substrate passage and exposure to the active sites within the proteolytic chamber of the 20S proteasome core particle (CP). MD simulations of the CP reveal relaxation dynamics in which the CP slowly contracts over the 54 ns sampling period. MD simulations of the SyringolinA (SylA) inhibitor within the proteolytic B 1 ring chamber of the CP indicate that favorable van der Waals and electrostatic interactions account for the predominant association of the inhibitor with the walls of the proteolytic chamber. The time scale required for the inhibitor to travel from the center of the proteolytic chamber to the chamber wall is on the order of 4 ns, accompanied by an average energetic stabilization of approximately −20 kcal/mol.

scholarly journals Polypharmacology of Some Medicinal Plant Metabolites Against SARS-CoV-2 and Host Targets: Molecular Dynamics Evaluation of NSP9 RNA Binding Protein

2020 ◽  
Author(s):  
Suritra Bandyopadhyay ◽  
Omobolanle Abimbola Abiodun ◽  
Blessing Chinweotito Ogboo ◽  
Adeola Tawakalitu Kola-Mustapha ◽  
Emmanuel Ifeanyi Attah ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Medicinal Plants ◽  
Active Sites ◽  
Rna Binding ◽  
Hydrophobic Interactions ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Receptor Interaction ◽  
Plant Metabolites ◽  
Structure Comparison

<p><b>Background: </b>Medicinal plants, as rich sources of bioactive compounds with antiviral properties, are now being explored for the development of drugs against SARS-CoV-2.</p><p><b>Aims: </b>Identification of promising compounds for the treatment of COVID-19 from natural products via molecular modelling against NSP9, including some other viral and host targets and evaluation of polypharmacological indications.</p><p><b>Main methods: </b>A manually curated library of 521 phytochemicals (from 19 medicinal plants) was virtually screened using Mcule server and binding interactions were studied using DS Visualiser. Docking thresholds were set based on the scores of standard controls and rigorous ADMET properties were used to finally get the potential inhibitors. Free binding energies of the docked complexes were calculated employing MM-GBSA method. MM-GBSA informed our choice for MD simulation studies performed against NSP9 to study the stability of the drug-receptor interaction. NSP9 structure comparison was also performed. </p><p><b>Key findings: </b>Extensive screening of the molecules identified 5 leads for NSP9, 23 for Furin, 18 for ORF3a, and 19 for interleukin-6. Ochnaflavone and Licoflavone B, obtained from Lonicera japonica (Japanese Honeysuckle) and Glycyrrhiza glabra (Licorice), respectively, were identified to have the highest potential multi-target inhibition properties for NSP9, furin, ORF3a, and IL-6. Additionally, molecular dynamics simulation supports the robust stability of Ochnaflavone and Licoflavone B against NSP9 at the active sites via hydrophobic interactions, H-bonding, and H-bonding facilitated by water.</p><b>Significance:</b> These compounds with the highest drug-like ranking against multiple viral and host targets have the potential to be drug candidates for the treatment of SARS-CoV-2 infection that may possibly act on multiple pathways simultaneously to inhibit viral entry and replication as well as disease progression.

scholarly journals A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

2021 ◽  
Author(s):  
Raymond Owens ◽  
Jiandong Huo ◽  
Halina Mikolajek ◽  
Audrey Le Bas ◽  
Jordan Clark ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Unmet Need ◽  
Spike Protein ◽  
Protein Crystal ◽  
Hamster Model ◽  
Cryo Electron Microscopy ◽  
Effective Prophylaxis ◽  
Escape Mutants ◽  
Single Domain Antibodies ◽  
Global Threat

Abstract SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We report four nanobodies (C5, H3, C1, F2) engineered as homotrimers with pmolar affinity for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Crystal structures show C5 and H3 overlap the ACE2 epitope, whilst C1 and F2 bind to a different epitope. Cryo Electron Microscopy shows C5 binding results in an all down arrangement of the Spike protein. C1, H3 and C5 all neutralize the Victoria strain, and the highly transmissible Alpha (B.1.1.7 first identified in Kent, UK) strain and C1 also neutralizes the Beta (B.1.35, first identified in South Africa). Administration of C5-trimer via the respiratory route showed potent therapeutic efficacy in the Syrian hamster model of COVID-19 and separately effective prophylaxis. The molecule was similarly potent by intraperitoneal injection.

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