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 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 Identification of Potential Phytochemical Inhibitors as Promising Therapeutics Against SARS-CoV-2 and Molecular Dynamics Simulation

2020 ◽  
Author(s):  
Anik Banik ◽  
Emran Sajib ◽  
Anamika Deb ◽  
Sheikh Rashel Ahmed ◽  
Md- Tariqul Islam ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Rna Binding ◽  
Viral Infections ◽  
Dynamics Simulation ◽  
Screening Methods ◽  
Plant Metabolites ◽  
Target Class ◽  
Drug Candidates ◽  
Preventive Medication

The high infectivity and mortality of novel coronavirus has caused a serious concern all over the world. Still, there is no specific drug or preventive medication to treat SARS-CoV-2 infection despite comprehensive analysis by the researchers. This study was designed to demonstrate the efficacy of some phyto-chemical compounds against SARS-CoV-2 by using both structure and ligand based virtual screening methods. A total of 33 plant metabolites were screened against SARS-CoV-2 main protease proteins (MPP), Nsp9 RNA binding protein, spike receptor binding domain and HR2 domain using a molecular docking approach. Results showed that three metabolites, i.e., Limonin, Isoflavone, and Coumadin conferred maximum binding affinity with all key proteins of SARS-CoV-2. For each viral protein, the critical binding sites and drug surface hotspots have been unraveled. ADME analysis indicated that none of the compounds have adverse effects that could decrease their drug-like properties. Moreover, toxicity pattern analysis also unmasked the non-toxic nature of the top drug candidates. The RMSD values of top ligandmacromolecule complexes were less than 2 Å, while RMSF values showed regular atomic fluctuations in the molecular dynamics study. Notably, most of the target class by top drug candidates belonged to enzyme groups (e.g. oxidoreductases, protease, Kinase). Results of drug similarity prediction revealed two approved structural analogs of Coumadin named Warfarin (DB00682) and Phenprocoumon (DB00946) from DrugBank. In addition, Isoformononetin an experimental drug analog of isoflavone could also be an option for the treatment of viral infections. For limonin there was no analog found in drugbank. The study can pave the way for the creation of effective SARS-CoV-2 medications and preventive measures. We highly recommend further in vivo trials for the experimental validation of our findings

scholarly journals Identification of Potential Phytochemical Inhibitors as Promising Therapeutics Against SARS-CoV-2 and Molecular Dynamics Simulation

2020 ◽  
Author(s):  
Anik Banik ◽  
Emran Sajib ◽  
Anamika Deb ◽  
Sheikh Rashel Ahmed ◽  
Md- Tariqul Islam ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Rna Binding ◽  
Viral Infections ◽  
Dynamics Simulation ◽  
Screening Methods ◽  
Plant Metabolites ◽  
Target Class ◽  
Drug Candidates ◽  
Preventive Medication

The high infectivity and mortality of novel coronavirus has caused a serious concern all over the world. Still, there is no specific drug or preventive medication to treat SARS-CoV-2 infection despite comprehensive analysis by the researchers. This study was designed to demonstrate the efficacy of some phyto-chemical compounds against SARS-CoV-2 by using both structure and ligand based virtual screening methods. A total of 33 plant metabolites were screened against SARS-CoV-2 main protease proteins (MPP), Nsp9 RNA binding protein, spike receptor binding domain and HR2 domain using a molecular docking approach. Results showed that three metabolites, i.e., Limonin, Isoflavone, and Coumadin conferred maximum binding affinity with all key proteins of SARS-CoV-2. For each viral protein, the critical binding sites and drug surface hotspots have been unraveled. ADME analysis indicated that none of the compounds have adverse effects that could decrease their drug-like properties. Moreover, toxicity pattern analysis also unmasked the non-toxic nature of the top drug candidates. The RMSD values of top ligandmacromolecule complexes were less than 2 Å, while RMSF values showed regular atomic fluctuations in the molecular dynamics study. Notably, most of the target class by top drug candidates belonged to enzyme groups (e.g. oxidoreductases, protease, Kinase). Results of drug similarity prediction revealed two approved structural analogs of Coumadin named Warfarin (DB00682) and Phenprocoumon (DB00946) from DrugBank. In addition, Isoformononetin an experimental drug analog of isoflavone could also be an option for the treatment of viral infections. For limonin there was no analog found in drugbank. The study can pave the way for the creation of effective SARS-CoV-2 medications and preventive measures. We highly recommend further in vivo trials for the experimental validation of our findings

scholarly journals In silico screening of hundred phytocompounds of ten medicinal plants as potential inhibitors of nucleocapsid phosphoprotein of COVID-19: An approach to prevent virus assembly

2020 ◽  
Author(s):  
Rajan Rolta ◽  
Rohitash Yadav ◽  
Deeksha Salaria ◽  
Anuradha Sourirajan ◽  
Kamal Dev
Keyword(s):  
Medicinal Plants ◽  
Active Sites ◽  
Rna Binding ◽  
Virus Assembly ◽  
Specific Treatment ◽  
Binding Domain ◽  
Binding Energies ◽  
Receptor Protein ◽  
Aloe Emodin ◽  
Rna Binding Domain

Abstract Currently, there is no specific treatment to cure COVID-19. Many medicinal plants have antiviral, antioxidant, antibacterial, antifungal, anticancer, wound healing etc. Therefore, the aim of the current study was to screen for potent inhibitors of N-terminal domain (NTD) of nucleocapsid phosphoproteinof SARS-CoV-2. The structure of NTD of RNA binding domain of nucleocapsid phosphoprotein of SARS coronavirus 2 was retrieved from the Protein Data Bank (PDB 6VYO)and the structures of 100 different phytocompoundswere retrieved from Pubchem. The receptor protein and ligands were prepared using Schrodinger’s Protein Preparation Wizard. Molecular docking was done by using the Schrodinger’s maestro 12.0 software. Drug likeness and toxicity of active phytocompounds was predicted by using Swiss adme, admetSAR and protox II online servers. We have identified three potential active sites (named as A, B, C) on receptor protein for efficient binding of the phytocompounds. We found that, among 100 phytocompounds, emodin, aloe-emodin, anthrarufin, alizarine, and dantron of Rheum emodi showed good binding affinity at all the three active sites of RNA binding domain of nucleocapsid phosphoprotein of COVID-19.The binding energies of emodin, aloe-emodin, anthrarufin, alizarine, and dantron were -8.299 , -8.508, -8.456, -8.441, and -8.322 Kcal mol-1 respectively (site A), -7.714, -6.433, -6.354, -6.598, and -6.99 Kcal mol-1 respectively (site B), and -8.299, 8.508, 8.538, 8.841, and 8.322 Kcal mol-1 respectively (site C).All the active phytocompounds follows the drug likeness properties, non-carcinogenic, and non-toxic. Theses phytocompounds (alone or in combination) could be developed into effective therapy against COVID-19.

scholarly journals Structure-based virtual screening suggests inhibitors of 3-Chymotrypsin-Like Protease of SARS-CoV-2 from Vernonia amygdalina and Occinum gratissimum

2021 ◽  
Author(s):  
Gideon A. Gyebi ◽  
Abdo A. Elfiky ◽  
Oludare M. Ogunyemi ◽  
Ibrahim M. Ibrahim ◽  
Adegbenro P. Adegunloye ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
In Silico ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Intermediate Formation ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Energy Calculation ◽  
Vernonia Amygdalina

Abstract An in-house library of 173 phytocompound structures from Vernonia amygdalina and Occinum gratissimum was screened against the active region of 3-Chymotrypsin-Like Protease (3CLpro) of SARS-CoV-2 in silico. Based on docking scores and reference inhibitors, a hit- list of 21 phytocompounds, with binding energies ranging from − 7.2 to -8.0 kcal/mol, was initially generated. Further docking against the 3CLpro of related coronaviruses (SARS-CoV and MERS-CoV), docking to 5 different representative conformations generated from the cluster analysis of SARS-CoV-2 3CLpro molecular dynamics simulation (MDS) trajectories, and in silico drug-likeness analyses, revealed two drug-like terpenoid structures as promising non-covalent inhibitors of SARS-CoV-2 3CLPro viz: neoandrographolide and vernolide. These terpenoid structures are accommodated within the substrate-binding pocket, and interacted with the catalytic dyad, the oxyanion loop (residues 138–145), and the S1/S2 subsites of the enzyme active site. With the aid of an array of hydrogen bonds and hydrophobic interactions with residues 142–145, these phytocompounds may stabilize the conformation of the flexible oxyanion loop; and thereby interfere with the tetrahedral oxyanion intermediate formation during proteolytic cleavage. Molecular dynamics simulation and binding free energy calculation further revealed that the terpenoid-enzyme complexes exhibit strong interactions and structural stability, which could be adapted for experimental models.

scholarly journals Screening marine algae metabolites as high-affinity inhibitors of SARS-CoV-2 main protease (3CLpro): an in silico analysis to identify novel drug candidates to combat COVID-19 pandemic

2020 ◽  
Vol 63 (1) ◽  
Author(s):  
Ghazala Muteeb ◽  
Adil Alshoaibi ◽  
Mohammad Aatif ◽  
Md. Tabish Rehman ◽  
M. Zuhaib Qayyum
Keyword(s):  
Hydrophobic Interactions ◽  
In Silico Analysis ◽  
Salt Bridge ◽  
Competitive Inhibitor ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
In Vivo Studies ◽  
Energy Calculation

AbstractThe recent dissemination of SARS-CoV-2 from Wuhan city to all over the world has created a pandemic. COVID-19 has cost many human lives and created an enormous economic burden. Although many drugs/vaccines are in different stages of clinical trials, still none is clinically available. We have screened a marine seaweed database (1110 compounds) against 3CLpro of SARS-CoV-2 using computational approaches. High throughput virtual screening was performed on compounds, and 86 of them with docking score <  − 5.000 kcal mol−1 were subjected to standard-precision docking. Based on binding energies (< − 6.000 kcal mol−1), 9 compounds were further shortlisted and subjected to extra-precision docking. Free energy calculation by Prime-MM/GBSA suggested RC002, GA004, and GA006 as the most potent inhibitors of 3CLpro. An analysis of ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of RC002, GA004, and GA006 indicated that only RC002 (callophysin A, from red alga Callophycus oppositifolius) passed Lipinski’s, Veber’s, PAINS and Brenk’s filters and displayed drug-like and lead-like properties. Analysis of 3CLpro-callophysin A complex revealed the involvement of salt bridge, hydrogen bonds, and hydrophobic interactions. callophysin A interacted with the catalytic residues (His41 and Cys145) of 3CLpro; hence it may act as a mechanism-based competitive inhibitor. Docking energy and docking affinity of callophysin A towards 3CLpro was − 8.776 kcal mol−1 and 2.73 × 106 M−1, respectively. Molecular dynamics simulation confirmed the stability of the 3CLpro-callophysin A complex. The findings of this study may serve as the basis for further validation by in vitro and in vivo studies.

Computational Discovery of SARS-CoV-2 NSP 16 Drug Candidates Based on Pharmacophore Modeling and Molecular Dynamics Simulation

2021 ◽  
Vol 20 (04) ◽  
pp. 377-390
Author(s):  
Zahra Hesari ◽  
Samaneh Zolghadri ◽  
Sajad Moradi ◽  
Mohsen Shahlaei ◽  
Elham Tazikeh-Lemeski
Keyword(s):  
Molecular Dynamics ◽  
Study Drug ◽  
Pharmacophore Modeling ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Structural Protein ◽  
Drug Candidates ◽  
Computational Discovery ◽  
Approved Drugs ◽  
Dynamics Simulations

Non-Structural Protein 16 (NSP-16) is one of the most suitable targets for discovery of drugs for corona viruses including SARS-CoV-2. In this study, drug discovery of SARS-CoV-2 nsp-16 has been accomplished by pharmacophore-based virtual screening among some analogs (FDA approved drugs) and marine natural plants (MNP). The comparison of the binding energies and the inhibition constants was determined using molecular docking method. Three compounds including two FDA approved (Ibrutinib, Idelalisib) and one MNP (Kumusine) were selected for further investigation using the molecular dynamics simulations. The results indicated that Ibrutinib and Idelalisib are oral medications while Kumusine, with proper hydrophilic and solubility properties, is an appropriate candidate for nsp-16 inhibitor and can be effective to control COVID-19 disease.

MOLECULAR MODELING OF THE INTERACTIONS BETWEEN HISTONE DEACETYLASE 8 AND INHIBITORS

2012 ◽  
Vol 11 (04) ◽  
pp. 907-924 ◽  
Author(s):  
DAWEI HUANG ◽  
XIAOHUI LI ◽  
ZHILONG XIU
Keyword(s):  
Molecular Dynamics ◽  
Histone Deacetylases ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Zinc Ion ◽  
Dynamics Simulation ◽  
Amino Acid Residues ◽  
Domain Docking ◽  
Dynamics Simulations ◽  
Linker Domain

Inhibitors of histone deacetylases (HDACs) have become an attractive class of anticancer agent. To understand the interaction between HDAC8 and inhibitors, including "pan-" inhibitors that inhibit many HDACs isoforms and selective inhibitors with no linker domain, docking and molecular dynamics simulation were conducted. Docking results showed the presence of π-π interactions between "linkerless" inhibitors and the aromatic amino acid residues of HDAC8 in the active site. Binding between HDAC8 and inhibitors was also stabilized by hydrogen bond and hydrophobic interaction. In molecular dynamics simulations, the zinc ion was shown to coordinate one more atom of HDAC8-"linkerless" inhibitor complexes than HDAC8-"pan-" inhibitor complexes. Persistent hydrogen bonds also existed between Tyr306 of HDAC8 and some inhibitors. When inhibitors with large cap groups bound to the active pocket of HDAC8, Phe152 and Met274 shifted from their initial positions and the entrance of the active pocket became more open, resulting in the formation of sub-pocket. Hydrophobic interactions contributed most favorably to the binding free energy between HDAC8 and inhibitors. Lys33, Asp178, Asp267, Tyr306 and Leu308 of HDAC8 were favorable for binding with all inhibitors.

scholarly journals Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

2019 ◽  
Vol 15 ◽  
pp. 1933-1944 ◽  
Author(s):  
Silvie Rimpelová ◽  
Michal Jurášek ◽  
Lucie Peterková ◽  
Jiří Bejček ◽  
Vojtěch Spiwok ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Biological Effects ◽  
Sesquiterpene Lactones ◽  
Living Cells ◽  
Calcium Atpase ◽  
Dynamics Simulation ◽  
Plant Metabolites ◽  
Cytotoxic Effects ◽  
Secondary Plant Metabolites ◽  
Fluorescent Derivative

Sesquiterpene lactones are secondary plant metabolites with sundry biological effects. In plants, they are synthesized, among others, for pesticidal and antimicrobial effects. Two such compounds, archangelolide and trilobolide of the guaianolide type, are structurally similar to the well-known and clinically tested lactone thapsigargin. While trilobolide has already been studied by us and others, there are only scarce reports on the biological activity of archangelolide. Here we present the preparation of its fluorescent derivative based on a dansyl moiety using azide–alkyne Huisgen cycloaddition having obtained the two sesquiterpene lactones from the seeds of Laserpitium archangelica Wulfen using supercritical CO2 extraction. We show that dansyl-archangelolide localizes in the endoplasmic reticulum of living cells similarly to trilobolide; localization in mitochondria was also detected. This led us to a more detailed study of the anticancer potential of archangelolide. Interestingly, we found that neither archangelolide nor its dansyl conjugate did exhibit cytotoxic effects in contrast to the structurally closely related counterparts trilobolide and thapsigargin. We explain this observation by a molecular dynamics simulation, in which, in contrast to trilobolide, archangelolide did not bind into the sarco/endoplasmic reticular calcium ATPase cavity utilized by thapsigargin. Last, but not least, archangelolide exhibited anti-inflammatory activity, which makes it promising compound for medicinal purposes.

scholarly journals Effect of Lysyllysine on non-covalent hybridization of single walled carbon nanotube by single-stranded DNA homodimer: in silico approach

2019 ◽  
Vol 9 (4) ◽  
pp. 315-321
Author(s):  
Fateme Bagherolhashemi ◽  
Mohammad Reza Bozorgmehr ◽  
Mohammad Momen-Heravi
Keyword(s):  
Molecular Dynamics ◽  
Carbon Nanotube ◽  
Electrostatic Interactions ◽  
Membered Ring ◽  
Binding Energies ◽  
Van Der Waals Interactions ◽  
Dynamics Simulation ◽  
Quantum Calculations ◽  
Single Walled Carbon Nanotube ◽  
Sensor Properties

Abstract In this work, the interactions between adenine–adenine di-nucleotide (DA2N) and carbon nanotube (CNT) in the presence of Lysyllysine (LL) was studied by the molecular dynamics simulation. Different carbon nanotubes including (5.5), (6.6) and (7.7) were used to investigate the effect of CNT type. The binding energies were calculated using the molecular mechanics-Poisson Bolzmann surface area method. The results showed that the contribution of the van der Waals interactions between DA2N and CNT was greater than that of the electrostatic interactions. The LL significantly enhanced the electrostatic interactions between the DA2N and CNT (6.6). The quantum calculations revealed that the sensor properties of the DA2N were not significantly affected by the CNT and LL. However, the five-membered ring of adenine played a more important role in the sensing properties of the DA2N. The obtained results are consistent with the previous experimental observations that can help to understand the molecular mechanism of the interaction of DA2N with CNT. Graphic abstract

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