scholarly journals Compounds Identified from Marine Mangrove Plant (Avicennia alba) as Potential Antiviral Drug Candidates against WDSV, an In-Silico Approach

Marine Drugs ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. 253
Author(s):  
Mohammed Othman Aljahdali ◽  
Mohammad Habibur Rahman Molla ◽  
Foysal Ahammad
Keyword(s):  
Md Simulation ◽  
Computational Study ◽  
Protein Structures ◽  
Antiviral Drug ◽  
Maturation Process ◽  
Gag Protein ◽  
Drug Candidates ◽  
Gag Polyprotein ◽  
Marine Plant ◽  
Avicennia Alba

Walleye dermal sarcoma virus (WDSV) is a type of retrovirus, which affects most of the adult walleye fishes during the spawning time. The virus causes multiple epithelial tumors on the fish’s skin and fins that are liable for more than 50% of the mortality rate of fish around the world. Till now, no effective antiviral drug or vaccine candidates have been developed that can block the progression of the disease caused by the pathogen. It was found that the 582-amino-acid (aa) residues long internal structural gag polyprotein of the virus plays an important role in virus budding and virion maturation outside of the cell. Inhibition of the protein can block the budding and virion maturation process and can be developed as an antiviral drug candidate against the virus. Therefore, the study aimed to identify potential natural antiviral drug candidates from the tropical mangrove marine plant Avicennia alba, which will be able to block the budding and virion maturation process by inhibiting the activity of the gag protein of the virus. Initially, a homology modeling approach was applied to identify the 3D structure, followed by refinement and validation of the protein. The refined protein structures were then utilized for molecular docking simulation. Eleven phytochemical compounds have been isolated from the marine plant and docked against the virus gag polyprotein. Three compounds, namely Friedlein (CID244297), Phytosterols (CID12303662), and 1-Triacontanol (CID68972) have been selected based on their docking score −8.5 kcal/mol, −8.0 kcal/mol and −7.9 kcal/mol, respectively, and were evaluated through ADME (Absorption, Distribution, Metabolism and Excretion), and toxicity properties. Finally, molecular dynamics (MD) simulation was applied to confirm the binding stability of the protein-ligands complex structure. The ADME and toxicity analysis reveal the efficacy and non-toxic properties of the compounds, where MD simulation confirmed the binding stability of the selected three compounds with the targeted protein. This computational study revealed the virtuous value of the selected three compounds against the targeted gag polyprotein and will be effective and promising antiviral candidates against the pathogen in a significant and worthwhile manner. Although in vitro and in vivo study is required for further evaluation of the compounds against the targeted protein.

scholarly journals Viruses and Type 1 Diabetes: From Enteroviruses to the Virome

2021 ◽  
Vol 9 (7) ◽  
pp. 1519
Author(s):  
Sonia R. Isaacs ◽  
Dylan B. Foskett ◽  
Anna J. Maxwell ◽  
Emily J. Ward ◽  
Clare L. Faulkner ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Viral Infections ◽  
Antiviral Drug ◽  
Virus Detection ◽  
Detection Methods ◽  
Islet Autoimmunity ◽  
Comprehensive Overview ◽  
Drug Candidates

For over a century, viruses have left a long trail of evidence implicating them as frequent suspects in the development of type 1 diabetes. Through vigorous interrogation of viral infections in individuals with islet autoimmunity and type 1 diabetes using serological and molecular virus detection methods, as well as mechanistic studies of virus-infected human pancreatic β-cells, the prime suspects have been narrowed down to predominantly human enteroviruses. Here, we provide a comprehensive overview of evidence supporting the hypothesised role of enteroviruses in the development of islet autoimmunity and type 1 diabetes. We also discuss concerns over the historical focus and investigation bias toward enteroviruses and summarise current unbiased efforts aimed at characterising the complete population of viruses (the “virome”) contributing early in life to the development of islet autoimmunity and type 1 diabetes. Finally, we review the range of vaccine and antiviral drug candidates currently being evaluated in clinical trials for the prevention and potential treatment of type 1 diabetes.

scholarly journals Gold (III) Derivatives in Colon Cancer Treatment

2022 ◽  
Vol 23 (2) ◽  
pp. 724
Author(s):  
Agata Gurba ◽  
Przemysław Taciak ◽  
Mariusz Sacharczuk ◽  
Izabela Młynarczuk-Biały ◽  
Magdalena Bujalska-Zadrożny ◽  
...  
Keyword(s):  
Protein Structures ◽  
Thioredoxin Reductase ◽  
Structural Similarity ◽  
In Vivo Studies ◽  
Antitumor Effects ◽  
Solubility In Water ◽  
Physiological Conditions ◽  
Drug Candidates ◽  
New Methods

Cancer is one of the leading causes of morbidity and mortality worldwide. Colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the second in women. Standard patterns of antitumor therapy, including cisplatin, are ineffective due to their lack of specificity for tumor cells, development of drug resistance, and severe side effects. For this reason, new methods and strategies for CRC treatment are urgently needed. Current research includes novel platinum (Pt)- and other metal-based drugs such as gold (Au), silver (Ag), iridium (Ir), or ruthenium (Ru). Au(III) compounds are promising drug candidates for CRC treatment due to their structural similarity to Pt(II). Their advantage is their relatively good solubility in water, but their disadvantage is an unsatisfactory stability under physiological conditions. Due to these limitations, work is still underway to improve the formula of Au(III) complexes by combining with various types of ligands capable of stabilizing the Au(III) cation and preventing its reduction under physiological conditions. This review summarizes the achievements in the field of stable Au(III) complexes with potential cytotoxic activity restricted to cancer cells. Moreover, it has been shown that not nucleic acids but various protein structures such as thioredoxin reductase (TrxR) mediate the antitumor effects of Au derivatives. The state of the art of the in vivo studies so far conducted is also described.

scholarly journals Crystal structure of the adenosine A2Areceptor bound to an antagonist reveals a potential allosteric pocket

2017 ◽  
Vol 114 (8) ◽  
pp. 2066-2071 ◽  
Author(s):  
Bingfa Sun ◽  
Priti Bachhawat ◽  
Matthew Ling-Hon Chu ◽  
Martyn Wood ◽  
Tom Ceska ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Protein Structures ◽  
Binding Pocket ◽  
Cubic Phase ◽  
Receptor Subtype ◽  
Type I ◽  
Intracellular Loop ◽  
Drug Candidates

The adenosine A2Areceptor (A2AR) has long been implicated in cardiovascular disorders. As more selective A2AR ligands are being identified, its roles in other disorders, such as Parkinson’s disease, are starting to emerge, and A2AR antagonists are important drug candidates for nondopaminergic anti-Parkinson treatment. Here we report the crystal structure of A2Areceptor bound to compound 1 (Cmpd-1), a novel A2AR/N-methyld-aspartate receptor subtype 2B (NR2B) dual antagonist and potential anti-Parkinson candidate compound, at 3.5 Å resolution. The A2Areceptor with a cytochrome b562-RIL (BRIL) fusion (A2AR–BRIL) in the intracellular loop 3 (ICL3) was crystallized in detergent micelles using vapor-phase diffusion. Whereas A2AR–BRIL bound to the antagonist ZM241385 has previously been crystallized in lipidic cubic phase (LCP), structural differences in the Cmpd-1–bound A2AR–BRIL prevented formation of the lattice observed with the ZM241385–bound receptor. The crystals grew with a type II crystal lattice in contrast to the typical type I packing seen from membrane protein structures crystallized in LCP. Cmpd-1 binds in a position that overlaps with the native ligand adenosine, but its methoxyphenyl group extends to an exosite not previously observed in other A2AR structures. Structural analysis revealed that Cmpd-1 binding results in the unique conformations of two tyrosine residues, Tyr91.35and Tyr2717.36, which are critical for the formation of the exosite. The structure reveals insights into antagonist binding that are not observed in other A2AR structures, highlighting flexibility in the binding pocket that may facilitate the development of A2AR-selective compounds for the treatment of Parkinson’s disease.

scholarly journals Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

Science ◽  
2020 ◽  
Vol 368 (6497) ◽  
pp. 1331-1335 ◽  
Author(s):  
Wenhao Dai ◽  
Bing Zhang ◽  
Xia-Ming Jiang ◽  
Haixia Su ◽  
Jian Li ◽  
...  
Keyword(s):  
Antiviral Drug ◽  
X Ray ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Main Protease ◽  
Pharmacokinetic Properties ◽  
Key Enzyme ◽  
Low Toxicity ◽  
Aldehyde Groups

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, Mpro, is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti–SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of 11a and 11b are covalently bound to cysteine 145 of Mpro. Both compounds showed good pharmacokinetic properties in vivo, and 11a also exhibited low toxicity, which suggests that these compounds are promising drug candidates.

scholarly journals Molecular Dynamics Simulation reveals the mechanism by which the Influenza Cap-dependent Endonuclease acquires resistance against Baloxavir marboxil

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ryunosuke Yoshino ◽  
Nobuaki Yasuo ◽  
Masakazu Sekijima
Keyword(s):  
Molecular Dynamics ◽  
Aromatic Ring ◽  
Influenza A ◽  
Md Simulation ◽  
Binding Free Energy ◽  
Complex Structure ◽  
Antiviral Drug ◽  
Rna Replication ◽  
Dynamics Simulation ◽  
Dependent Endonuclease

AbstractBaloxavir marboxil (BXM), an antiviral drug for influenza virus, inhibits RNA replication by binding to RNA replication cap-dependent endonuclease (CEN) of influenza A and B viruses. Although this drug was only approved by the FDA in October 2018, drug resistant viruses have already been detected from clinical trials owing to an I38 mutation of CEN. To investigate the reduction of drug sensitivity by the I38 mutant variants, we performed a molecular dynamics (MD) simulation on the CEN-BXM complex structure to analyze variations in the mode of interaction. Our simulation results suggest that the side chain methyl group of I38 in CEN engages in a CH-pi interaction with the aromatic ring of BXM. This interaction is abolished in various I38 mutant variants. Moreover, MD simulation on various mutation models and binding free energy prediction by MM/GBSA method suggest that the I38 mutation precludes any interaction with the aromatic ring of BXA and thereby reduces BXA sensitivity.

Computational study on transfer of L-ascorbic acid by UlaA throughEscherichia colimembrane

2017 ◽  
Vol 15 (03) ◽  
pp. 1750007 ◽  
Author(s):  
Ehsan Faghih-Mirzaee ◽  
Maryam Dehestani ◽  
Leila Zeidabadinejad
Keyword(s):  
Ascorbic Acid ◽  
Molecular Docking ◽  
Active Sites ◽  
Density Functional ◽  
Md Simulation ◽  
Computational Study ◽  
Radius Of Gyration ◽  
Internal Cavity ◽  
Chemical Hardness ◽  
E Coli

In this study, the transfer of L-ascorbic acid by UlaA through Escherichia coli (E. coli) membrane was evaluated using density functional theory (DFT), molecular docking, and molecular dynamics (MD) simulation methods. DFT calculations at the B3lyp/6[Formula: see text]311[Formula: see text]G(p,d) level were performed to investigate the interaction properties and molecular descriptors. The physical properties, such as chemical potential, chemical hardness, and chemical electrophilicity of all studied molecules, were investigated. Natural population analysis was employed to describe the state of charge transfer between interactions using the natural bond orbital (NBO). The atoms in molecules (AIM) theory was used to examine the properties of the bond critical points such as their electron densities and Laplacians. Molecular docking studies showed that L-ascorbic acid was bounded to the internal cavity of UlaA. It was found that there were some hydrogen bond interactions between L-ascorbic acid and active sites of UlaA. The results of the MD simulation showed that the root mean square deviation (RMSD) of UlaA and L-ascorbic acid bound-UlaA reached equilibrium after 3.7[Formula: see text]ns. An evaluation of the radius of gyration ([Formula: see text]) revealed that UlaA and L-ascorbic acid bound-UlaA were stabilized around 10,000[Formula: see text]ns. Finally, analysis of the RMS fluctuations suggested that the structure of the L-ascorbic acid binding site remained approximately rigid during simulation. All obtained results shed light on the special manner of L-ascorbic acid transfer through E. coli membrane, and confirmed the results of previous studies on this issue.

Computational Study of Optical Properties of Cellulose Triacetate Film

2013 ◽  
Vol 1524 ◽  
Author(s):  
Daichi Hayakawa ◽  
Kazuyoshi Ueda
Keyword(s):  
Polymer Film ◽  
Density Functional ◽  
Md Simulation ◽  
Computational Study ◽  
Monomer Unit ◽  
Cellulose Triacetate ◽  
Functional Theory ◽  
Torsion Angles ◽  
Conformational Freedom ◽  
Intrinsic Birefringence

ABSTRACTThe birefringence of a cellulose triacetate (CTA) polymer film was evaluated based on density functional theory and molecular dynamics (MD) simulation. The polarizability of the monomer unit of CTA was initially calculated to determine the intrinsic properties of the birefringence of CTA. The most important conformational freedom of the CTA monomer unit is derived from the C-6 acetyl methyl groups. This exocyclic group is known to have three low energy conformers referred to as gg, gt, and tg according to the rotation of the different torsion angles. Because the polarizability can be viewed as dependent on the conformation of CTA, the polarizability of these three conformers was evaluated. The results demonstrated that negative intrinsic birefringence was associated with the CTA repeating units having gg or gt structures, whereas the monomer units with tg structures were characterized by positive intrinsic birefringence. A model of the polymer film was constructed based on MD simulation and the birefringence of the model was evaluated using the calculated monomer birefringence values. The birefringence of the CTA film was found to be negative because most of the CTA repeating units adopt the gg conformation in the film. The negative value of the simulated birefringence is in good agreement with the result obtained by the experiment.

scholarly journals Predicting glycosaminoglycan surface protein interactions and implications for studying axonal growth

2017 ◽  
Vol 114 (52) ◽  
pp. 13697-13702 ◽  
Author(s):  
Adam R. Griffith ◽  
Claude J. Rogers ◽  
Gregory M. Miller ◽  
Ravinder Abrol ◽  
Linda C. Hsieh-Wilson ◽  
...  
Keyword(s):  
Cell Surface ◽  
Chondroitin Sulfate ◽  
Protein Interactions ◽  
Neural Development ◽  
Structural Information ◽  
Protein Structures ◽  
Computational Method ◽  
Cns Injury ◽  
Gag Protein ◽  
Cord Injury

Cell-surface carbohydrates play important roles in numerous biological processes through their interactions with various protein-binding partners. These interactions are made possible by the vast structural diversity of carbohydrates and the diverse array of carbohydrate presentations on the cell surface. Among the most complex and important carbohydrates are glycosaminoglycans (GAGs), which display varied stereochemistry, chain lengths, and patterns of sulfation. GAG–protein interactions participate in neuronal development, angiogenesis, spinal cord injury, viral invasion, and immune response. Unfortunately, little structural information is available for these complexes; indeed, for the highly sulfated chondroitin sulfate motifs, CS-E and CS-D, there are no structural data. We describe here the development and validation of the GAG-Dock computational method to predict accurately the binding poses of protein-bound GAGs. We validate that GAG-Dock reproduces accurately (<1-Å rmsd) the crystal structure poses for four known heparin–protein structures. Further, we predict the pose of heparin and chondroitin sulfate derivatives bound to the axon guidance proteins, protein tyrosine phosphatase σ (RPTPσ), and Nogo receptors 1–3 (NgR1-3). Such predictions should be useful in understanding and interpreting the role of GAGs in neural development and axonal regeneration after CNS injury.

scholarly journals Distribution of genotype network sizes in sequence-to-structure genotype–phenotype maps

2017 ◽  
Vol 14 (129) ◽  
pp. 20160976 ◽  
Author(s):  
Susanna Manrubia ◽  
José A. Cuesta
Keyword(s):  
Dna Sequences ◽  
Computational Study ◽  
Protein Structures ◽  
Power Law Distribution ◽  
Rna Sequences ◽  
Qualitative And Quantitative ◽  
Alternative Phenotypes ◽  
Genotype Space ◽  
Quantitative Identification

An essential quantity to ensure evolvability of populations is the navigability of the genotype space. Navigability, understood as the ease with which alternative phenotypes are reached, relies on the existence of sufficiently large and mutually attainable genotype networks. The size of genotype networks (e.g. the number of RNA sequences folding into a particular secondary structure or the number of DNA sequences coding for the same protein structure) is astronomically large in all functional molecules investigated: an exhaustive experimental or computational study of all RNA folds or all protein structures becomes impossible even for moderately long sequences. Here, we analytically derive the distribution of genotype network sizes for a hierarchy of models which successively incorporate features of increasingly realistic sequence-to-structure genotype–phenotype maps. The main feature of these models relies on the characterization of each phenotype through a prototypical sequence whose sites admit a variable fraction of letters of the alphabet. Our models interpolate between two limit distributions: a power-law distribution, when the ordering of sites in the prototypical sequence is strongly constrained, and a lognormal distribution, as suggested for RNA, when different orderings of the same set of sites yield different phenotypes. Our main result is the qualitative and quantitative identification of those features of sequence-to-structure maps that lead to different distributions of genotype network sizes.

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