scholarly journals Design and Computational Analysis of a Chimeric Avian Influenza Antigen: A Yeast-displayed, Universal and Cross-protective Vaccine Candidate

2021 ◽  
Author(s):  
Elyas Mohammadi ◽  
Zana Pirkhezrian ◽  
Samira Dashti ◽  
Naghmeh Saedi ◽  
Mohammad Hadi Sekhavati
Keyword(s):  
Avian Influenza ◽  
Influenza Vaccine ◽  
Vaccine Candidate ◽  
Consensus Sequence ◽  
Md Simulations ◽  
Positive Control ◽  
Docking Studies ◽  
Binding Energies ◽  
Peptide Sequence ◽  
The Stability

Background: A cross-protective avian influenza vaccine candidate can be designed by using a preserved antigen against mutation in various subtypes of influenza. M2e peptide sequence has remained remarkably unchanged in influenza type A isolated since 1918. Methods: A consensus sequence of M2e peptide was obtained from 31 sequences of H5N8, H5N1, H9N2 and H7N9 subtypes of avian influenza virus isolated from 7 avian species in 5 Asian countries. A partial sequence of flagellin was considered as an adjuvant. Subsequently, two chimeric antigens were designed to be virtually cloned and expressed using PYD1 vector and EBY100 yeast strain. The stability and conformational features of these two antigens were assessed through molecular dynamic (MD) simulations. The detectability of vaccine candidates by a specific monoclonal antibody (MAb148) were estimated through docking studies. Results: In spite of significant compactness and stability of the first candidate in comparison with the second design, it was less detectable by MAb148. Contrary to the first chimeric antigen, Van der Waals, electrostatic and binding energies of the interaction of the second antigen with MAb148 were significantly closer to the positive control. It is shown that epitopes of the second chimeric antigen could be correctly located in the specific pocket of CDR region of MAb148. Conclusion: The second chimeric antigen could be considered as a yeast-displayed avian influenza vaccine candidate due to the capability of provoking humoral immunity and innate immune system by M2e and flagellin respectively.

scholarly journals Potential Smoothened Inhibitor from Traditional Chinese Medicine against the Disease of Diabetes, Obesity, and Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Mao-Feng Sun ◽  
Hsin-Yi Chen ◽  
Cheng-Chun Lee ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Drug Development ◽  
Hedgehog Signaling ◽  
Docking Simulation ◽  
Md Simulations ◽  
Positive Control ◽  
Lead Compounds ◽  
Oncology Clinical Trials ◽  
Body Patterning ◽  
The Stability ◽  
Smo Inhibitor

Nowadays, obesity becomes a serious global problem, which can induce a series of diseases such as type 2 diabetes mellitus, cancer, cardiovascular disease, metabolic syndrome, and stoke. For the mechanisms of diseases, the hedgehog signaling pathway plays an important role in body patterning during embryogenesis. For this reason, smoothened homologue (Smo) protein had been indicated as the drug target. In addition, the small-molecule Smo inhibitor had also been used in oncology clinical trials. To improve drug development of TCM compounds, we aim to investigate the potent lead compounds as Smo inhibitor from the TCM compounds in TCM Database@Taiwan. The top three TCM compounds, precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid), have displayed higher potent binding affinities than the positive control, LY2940680, in the docking simulation. After MD simulations, which can optimize the result of docking simulation and validate the stability of H-bonds between each ligand and Smo protein under dynamic conditions, top three TCM compounds maintain most of interactions with Smo protein, which keep the ligand binding stable in the binding domain. Hence, we propose precatorine, labiatic acid, and 2,2′-[benzene-1,4-diylbis(methanediyloxybenzene-4,1-diyl)]bis(oxoacetic acid) as potential lead compounds for further study in drug development process with the Smo protein.

scholarly journals GC-MS, LC-MS/MS, Docking and Molecular Dynamics Approaches to Identify Potential SARS-CoV-2 3-Chymotrypsin-Like Protease Inhibitors from Zingiber officinale Roscoe

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5230
Author(s):  
Muhammad Sulaiman Zubair ◽  
Saipul Maulana ◽  
Agustinus Widodo ◽  
Ramadanil Pitopang ◽  
Muhammad Arba ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Zingiber Officinale ◽  
Md Simulations ◽  
Positive Control ◽  
Binding Energies ◽  
Ms Analysis ◽  
Protease Enzyme ◽  
Zingiber Officinale Roscoe ◽  
Isolated Compound ◽  
Dynamics Simulations

This study aims to identify and isolate the secondary metabolites of Zingiber officinale using GC-MS, preparative TLC, and LC-MS/MS methods, to evaluate the inhibitory potency on SARS-CoV-2 3 chymotrypsin-like protease enzyme, as well as to study the molecular interaction and stability by using docking and molecular dynamics simulations. GC-MS analysis suggested for the isolation of terpenoids compounds as major compounds on methanol extract of pseudostems and rhizomes. Isolation and LC-MS/MS analysis identified 5-hydro-7, 8, 2′-trimethoxyflavanone (9), (E)-hexadecyl-ferulate (1), isocyperol (2), N-isobutyl-(2E,4E)-octadecadienamide (3), and nootkatone (4) from the rhizome extract, as well as from the leaves extract with the absence of 9. Three known steroid compounds, i.e., spinasterone (7), spinasterol (8), and 24-methylcholesta-7-en-3β-on (6), were further identified from the pseudostem extract. Molecular docking showed that steroids compounds 7, 8, and 6 have lower predictive binding energies (MMGBSA) than other metabolites with binding energy of −87.91, −78.11, and −68.80 kcal/mole, respectively. Further characterization on the single isolated compound by NMR showed that 6 was identified and possessed 75% inhibitory activity on SARS-CoV-2 3CL protease enzyme that was slightly different with the positive control GC376 (77%). MD simulations showed the complex stability with compound 6 during 100 ns simulation time.

Polysaccharide Structures in the Outer Mucilage of Arabidopsis Seeds Visualized by AFM

2020 ◽  
Author(s):  
MAK Williams ◽  
V Cornuault ◽  
AH Irani ◽  
VV Symonds ◽  
J Malmström ◽  
...  
Keyword(s):  
Average Length ◽  
American Chemical Society ◽  
Md Simulations ◽  
Chemical Society ◽  
Side Chains ◽  
Rhamnogalacturonan I ◽  
Afm Imaging ◽  
Minor Population ◽  
The Stability ◽  
A Minor

© 2020 American Chemical Society. Evidence is presented that the polysaccharide rhamnogalacturonan I (RGI) can be biosynthesized in remarkably organized branched configurations and surprisingly long versions and can self-assemble into a plethora of structures. AFM imaging has been applied to study the outer mucilage obtained from wild-type (WT) and mutant (bxl1-3 and cesa5-1) Arabidopsis thaliana seeds. For WT mucilage, ordered, multichain structures of the polysaccharide RGI were observed, with a helical twist visible in favorable circumstances. Molecular dynamics (MD) simulations demonstrated the stability of several possible multichain complexes and the possibility of twisted fibril formation. For bxl1-3 seeds, the imaged polymers clearly showed the presence of side chains. These were surprisingly regular and well organized with an average length of ∼100 nm and a spacing of ∼50 nm. The heights of the side chains imaged were suggestive of single polysaccharide chains, while the backbone was on average 4 times this height and showed regular height variations along its length consistent with models of multichain fibrils examined in MD. Finally, in mucilage extracts from cesa5-1 seeds, a minor population of chains in excess of 30 μm long was observed.

In silico Discovery of Resveratrol Analogues as Potential Agents in Treatment of Metabolic Disorders

2019 ◽  
Vol 25 (35) ◽  
pp. 3776-3783
Author(s):  
Nebojša Pavlović ◽  
Maja Đanić ◽  
Bojan Stanimirov ◽  
Svetlana Goločorbin-Kon ◽  
Karmen Stankov ◽  
...  
Keyword(s):  
In Silico ◽  
Metabolic Disorders ◽  
Partial Agonist ◽  
Aqueous Solubility ◽  
Structural Similarity ◽  
Data Bank ◽  
Docking Studies ◽  
Binding Energies ◽  
Molegro Virtual Docker ◽  
Ppar Γ

Background: Resveratrol was demonstrated to act as partial agonist of PPAR-γ receptor, which opens up the possibility for its use in the treatment of metabolic disorders. Considering the poor bioavailability of resveratrol, particularly due to its low aqueous solubility, we aimed to identify analogues of resveratrol with improved pharmacokinetic properties and higher binding affinities towards PPAR-γ. Methods: 3D structures of resveratrol and its analogues were retrieved from ZINC database, while PPAR-γ structure was obtained from Protein Data Bank. Docking studies were performed using Molegro Virtual Docker software. Molecular descriptors relevant to pharmacokinetics were calculated from ligand structures using VolSurf+ software. Results: Using structural similarity search method, 56 analogues of resveratrol were identified and subjected to docking analyses. Binding energies were ranged from -136.69 to -90.89 kcal/mol, with 16 analogues having higher affinities towards PPAR-γ in comparison to resveratrol. From the calculated values of SOLY descriptor, 23 studied compounds were shown to be more soluble in water than resveratrol. However, only two tetrahydroxy stilbene derivatives, piceatannol and oxyresveratrol, had both better solubility and affinity towards PPAR-γ. These compounds also had more favorable ADME profile, since they were shown to be more metabolically stable and wider distributed in body than resveratrol. Conclusion: Piceatannol and oxyresveratrol should be considered as potential lead compounds for further drug development. Although experimental validation of obtained in silico results is required, this work can be considered as a step toward the discovery of new natural and safe drugs in treatment of metabolic disorders.

Target Fishing of Calactin, Calotropin and Calotoxin Using Reverse Pharmacophore Screening and Consensus Inverse Docking Approach

2020 ◽  
Vol 17 ◽  
Author(s):  
Vikram Parthasarathy ◽  
Achuthan Raghava Menon ◽  
Basavaraj Devaranavadagi
Keyword(s):  
Interleukin 2 ◽  
Pharmacophore Model ◽  
Positive Control ◽  
Screening Strategy ◽  
Binding Energies ◽  
Cancer Drug ◽  
Model Matching ◽  
Potential Target ◽  
Anti Cancer ◽  
Docking Approach

Background: The anticancer properties of natural products calactin, calotropin and calotoxin are well established. However the mechanisms of their action are unclear and the molecular targets pertinent to them are not detailed. In this study, potential anti-cancer targets of these compounds have been identified using reverse screening approaches that may provide valuable insights into anti cancer drug development. Objective: To identify the potential anticancer targets of calactin, calotropin and calotoxin using reverse screening strategy. Methods: The ligands were screened for potential targets based on their shape similarity and pharmacophore model matching. The overlapping targets obtained from both methods were verified using reverse docking approach and validated by docking analysis. MM/PBSA calculation was performed to predict binding affinities between ligand and confirmed targets. Results: Interleukin-2 inducible T cell kinase [ITK] was confirmed as a potential target of calactin (Ki= -10.3 kcal/mol), calotropin (Ki= -8.7 kcal/mol) and calotoxin (Ki= -10.2 kcal/mol). The ligands interacted with hinge region residues such as Met438 and Asp500 which occupy the highly conserved ATP binding site. Binding energies of calactin (∆Ebind = -29.18 kJ/mol), calotropin (-28.57 kJ/mol) and calotoxin (-21.21 kJ/mol) with ITK were higher than (more negative) positive control sunitinib (-15.03 kJ/mol) and standard staurosporine (-21.09 kJ/mol). Besides this, Interstitial collagenase [MMP1] was confirmed as potential target of calotoxin (Ki= -8.2 kcal/mol).However the binding energy (∆Ebind = -11.89 kJ/mol) was lower compared to positive control batimastat (-21.07 kJ/mol). Conclusion: The results of this study confirmed ITK as a potential target for calactin, calotropin and calotoxin. These compounds can therefore be used as lead molecules for the development of novel ITK inhibitors, which may have immense therapeutic applications as immune-suppressants and as anticancer drugs.

Closing the gap: an atomistic structural and functional perspective of S. mansoni universal stress G4LZI3 protein in complex with phenolic compounds

2020 ◽  
Vol 17 ◽  
Author(s):  
Priscilla Masamba ◽  
Geraldene Munsamy ◽  
Abidemi Paul Kappo
Keyword(s):  
Phenolic Compounds ◽  
Conformational Changes ◽  
Stress Protein ◽  
Md Simulations ◽  
Binding Energies ◽  
Developmental Cycle ◽  
Structure Based Drug Design ◽  
Bioinformatic Tools ◽  
Drug Of Choice ◽  
Functional Perspective

Background: For decades, Praziquantel has been the undisputed drug of choice for all schistosome infections, but rising concerns due to the unelucidated mechanism of action of the drug and unavoidable reports of emerging drug resistant strains has necessitated the need for alternative treatment drug. Moreover, current apprehension has been reinforced by total dependence on the drug for treatment hence, the search for novel and effective anti-schistosomal drugs. Uses: This study made use of bioinformatic tools to determine the structural binding of the Universal G4LZI3 stress protein (USP) in complex with ten polyphenol compounds, thereby highlighting the effectiveness of these recently identified ‘lead’ molecules in the design of novel therapeutics targeted against schistosomiasis. Upregulation of the G4LZI3 USP throughout the schistosome multifaceted developmental cycle sparks interest in its potential role as a druggable target. The integration of in silico tools provides an atomistic perspective into the binding of potential inhibitors to target proteins. Conclusion: This study therefore, implemented the use of molecular dynamic (MD) simulations to provide functional and structural insight into key conformational changes upon binding of G4ZLI3 to these key phenolic compounds. Post-MD analyses revealed unique structural and conformational changes in the G4LZI3 protein in complex with curcumin and catechin respectively. These systems exhibited the highest binding energies, while the major interacting residues conserved in all the complexes provides a route map for structure-based drug design of novel compounds with enhanced inhibitory potency against the G4LZI3 protein. This study suggests an alternative approach for the development of anti-schistosomal drugs using natural compounds.

In Silico and in Vitro Evaluation of Deamidation Effects on the Stability of the Fusion Toxin DAB389IL-2

2019 ◽  
Vol 16 (4) ◽  
pp. 307-313 ◽  
Author(s):  
Nasrin Zarkar ◽  
Mohammad Ali Nasiri Khalili ◽  
Fathollah Ahmadpour ◽  
Sirus Khodadadi ◽  
Mehdi Zeinoddini
Keyword(s):  
In Silico ◽  
Catalytic Domain ◽  
Md Simulations ◽  
Special Importance ◽  
Native Form ◽  
Vitro Experiment ◽  
In Vitro Experiment ◽  
Pharmaceutical Protein ◽  
The Stability

Background: DAB389IL-2 (Denileukin diftitox) as an immunotoxin is a targeted pharmaceutical protein and is the first immunotoxin approved by FDA. It is used for the treatment of various kinds of cancer such as CTCL lymphoma, melanoma, and Leukemia but among all of these, treatment of CTCL has special importance. DAB389IL-2 consists of two distinct parts; the catalytic domain of Diphtheria Toxin (DT) that genetically fused to the whole IL-2. Deamidation is the most important reaction for chemical instability of proteins occurs during manufacture and storage. Deamidation of asparagine residues occurs at a higher rate than glutamine residues. The structure of proteins, temperature and pH are the most important factors that influence the rate of deamidation. Methods: Since there is not any information about deamidation of DAB389IL-2, we studied in silico deamidation by Molecular Dynamic (MD) simulations using GROMACS software. The 3D model of fusion protein DAB389IL-2 was used as a template for deamidation. Then, the stability of deamidated and native form of the drug was calculated. Results: The results of MD simulations were showed that the deamidated form of DAB389IL-2 is more unstable than the normal form. Also, deamidation was carried by incubating DAB389IL-2, 0.3 mg/ml in ammonium hydrogen carbonate for 24 h at 37o C in order to in vitro experiment. Conclusion: The results of in vitro experiment were confirmed outcomes of in silico study. In silico and in vitro experiments were demonstrated that DAB389IL-2 is unstable in deamidated form.

scholarly journals Nanotechnology-based approaches for targeting and delivery of drugs via Hexakis (m-PE) macrocycles

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Samaneh Pasban ◽  
Heidar Raissi
Keyword(s):  
Drug Delivery ◽  
Density Functional ◽  
Water Solution ◽  
Decomposition Analysis ◽  
Binding Energies ◽  
Energy Decomposition Analysis ◽  
Partial Density ◽  
High Propensity ◽  
The Stability ◽  
Novel Applications

AbstractHexakis (m-phenylene ethynylene) (m-PE) macrocycles, with aromatic backbones and multiple hydrogen-bonding side chains, had a very high propensity to self-assemble via H-bond and π–π stacking interactions to form nanotubular structures with defined inner pores. Such stacking of rigid macrocycles is leading to novel applications that enable the researchers to explored mass transport in the sub-nanometer scale. Herein, we performed density functional theory (DFT) calculations to examine the drug delivery performance of the hexakis dimer as a novel carrier for doxorubicin (DOX) agent in the chloroform and water solvents. Based on the DFT results, it is found that the adsorption of DOX on the carrier surface is typically physisorption with the adsorption strength values of − 115.14 and − 83.37 kJ/mol in outside and inside complexes, respectively, and so that the essence of the drug remains intact. The negative values of the binding energies for all complexes indicate the stability of the drug molecule inside and outside the carrier's cavities. The energy decomposition analysis (EDA) has also been performed and shown that the dispersion interaction has an essential role in stabilizing the drug-hexakis dimer complexes. To further explore the electronic properties of dox, the partial density of states (PDOS and TDOS) are calculated. The atom in molecules (AIM) and Becke surface (BS) methods are also analyzed to provide an inside view of the nature and strength of the H-bonding interactions in complexes. The obtained results indicate that in all studied complexes, H-bond formation is the driving force in the stabilization of these structures, and also chloroform solvent is more favorable than the water solution. Overall, our findings offer insightful information on the efficient utilization of hexakis dimer as drug delivery systems to deliver anti-cancer drugs.

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