scholarly journals In silico screening for natural ligands to non-structural nsp7 conformers of SARS coronaviruses

2020 ◽  
Author(s):  
Rafael Blasco ◽  
Julio Coll
Keyword(s):  
Chemical Properties ◽  
Clinical Work ◽  
Binding Pocket ◽  
Binding Affinities ◽  
Structural Protein ◽  
In Silico Screening ◽  
Natural Ligands ◽  
Final Optimization ◽  
Scoring Algorithms

<p>The non-structural protein 7 (nsp7) of Severe Acute Respiratory Syndrome (SARS) coronaviruses was selected as a new target to potentially interfere with viral replication. The nsp7s are uniquely conserved small coronavirus proteins having a critical, yet intriguing participation on the replication of the long viral RNA genome after complexing with nsp8 and nsp12. Drugs with potential to interfere with nsp7s have not been described yet. Despite the difficulties of having no previously defined binding pocket, high-throughput blind screening of more than one hundred thousand natural compounds < 400 Dalton of molecular weight docked against the nsp7.1ysy conformer identified hundreds of leads displaying predicted high binding-affinities by AutoDockVina. The leads were then docked to 14 nsp7 available conformers by two different binding scoring algorithms ( AutoDockVina-PyRx and HYDE-seeSAR), to identify consensus top-leads. Further predictive analysis of their physiological/toxicity ADMET criteria (chemical properties, adsorption, metabolism, toxicity) narrowed top-leads to a few drug-like ligands, most of them showing steroid-like structures closely related to some of those being actually used in clinical work. A final optimization by search for structural similarities to the drug-like top-lead, yielded a collection of novel steroid-like ligands with ~100-fold higher-affinity whose antiviral activity may be experimentally validated since they are available. Additionally, these nsp7-interacting ligands and/or their further optimized derivatives, may offer new tools to investigate the intriguing role of nsp7 on replication of coronaviruses<br></p>

scholarly journals In silico screening for natural ligands to non-structural nsp7 conformers of SARS coronaviruses

2020 ◽  
Author(s):  
Rafael Blasco ◽  
Julio Coll
Keyword(s):  
Chemical Properties ◽  
Clinical Work ◽  
Binding Pocket ◽  
Binding Affinities ◽  
Structural Protein ◽  
In Silico Screening ◽  
Natural Ligands ◽  
Final Optimization ◽  
Scoring Algorithms

<p>The non-structural protein 7 (nsp7) of Severe Acute Respiratory Syndrome (SARS) coronaviruses was selected as a new target to potentially interfere with viral replication. The nsp7s are uniquely conserved small coronavirus proteins having a critical, yet intriguing participation on the replication of the long viral RNA genome after complexing with nsp8 and nsp12. Drugs with potential to interfere with nsp7s have not been described yet. Despite the difficulties of having no previously defined binding pocket, high-throughput blind screening of more than one hundred thousand natural compounds < 400 Dalton of molecular weight docked against the nsp7.1ysy conformer identified hundreds of leads displaying predicted high binding-affinities by AutoDockVina. The leads were then docked to 14 nsp7 available conformers by two different binding scoring algorithms ( AutoDockVina-PyRx and HYDE-seeSAR), to identify consensus top-leads. Further predictive analysis of their physiological/toxicity ADMET criteria (chemical properties, adsorption, metabolism, toxicity) narrowed top-leads to a few drug-like ligands, most of them showing steroid-like structures closely related to some of those being actually used in clinical work. A final optimization by search for structural similarities to the drug-like top-lead, yielded a collection of novel steroid-like ligands with ~100-fold higher-affinity whose antiviral activity may be experimentally validated since they are available. Additionally, these nsp7-interacting ligands and/or their further optimized derivatives, may offer new tools to investigate the intriguing role of nsp7 on replication of coronaviruses<br></p>

scholarly journals In Silico Screening for Natural Ligands to Non-Structural Nsp7 Conformers of Coronaviruses

2020 ◽  
Author(s):  
Rafael Blasco ◽  
Julio Coll
Keyword(s):  
In Silico ◽  
Chemical Properties ◽  
Structural Similarity ◽  
Binding Pocket ◽  
Binding Affinities ◽  
Structural Protein ◽  
Autodock Vina ◽  
Natural Ligands ◽  
Final Optimization

<p>The non-structural protein 7 (nsp7) of Severe Acute Respiratory Syndrome (SARS) coronaviruses was selected as a new target to potentially interfere with viral replication. The nsp7s are one of the most conserved, unique and small coronavirus proteins having a critical, yet intriguing participation on the replication of the long viral RNA genome after complexing with nsp8 and nsp12. Despite the difficulties of having no previous binding pocket, two high-throughput virtual blind screening of 158240 natural compounds > 400 Da by AutoDock Vina against nsp7.1ysy identified 655 leads displaying predicted binding affinities between 10 to 1100 nM. The leads were then screened against 14 available conformations of nsp7 by both AutoDock Vina and seeSAR programs employing different binding score algorithms, to identify 20 consensus top-leads. Further <i>in silico</i> predictive analysis of physiological and toxicity ADMET criteria (chemical properties, adsorption, metabolism, toxicity) narrowed top-leads to a few drug-like ligands many of them showing steroid-like structures. A final optimization by search for structural similarity to the top drug-like ligand that were also commercially available, yielded a collection of predicted novel ligands with ~100-fold higher-affinity whose antiviral activity may be experimentally validated. Additionally, these novel nsp7-interacting ligands and/or their further optimized derivatives, may offer new tools to investigate the intriguing role of nsp7 on replication of coronaviruses.</p>

Characteristics Of The Structure Formation Of Gypsum Binder Modified With Zinc Hydrosilicates

2020 ◽  
pp. 40-46
Keyword(s):  
Synergistic Effect ◽  
Physicochemical Properties ◽  
Structure Formation ◽  
Silicic Acid ◽  
Chemical Properties ◽  
Crystal Formation ◽  
Ability To Act ◽  
Chemical Factors ◽  
Sorption Characteristics

The authors' methodic for assessing the role of chemical and physic-chemical factors during the structure formation of gypsum stone is presented in the article. The methodic is also makes it possible to reveal the synergistic effect and to determine the ranges of variation of controls factors that ensure maximum values of such effect. The effect of a micro-sized modifier based on zinc hydro-silicates on the structure formation of building gypsum is analyzed and corresponding dependencies are found. It is shown that effects of influence of modifier on the properties of gypsum compositions are determined by chemical properties of modifier. Among the mentioned properties are sorption characteristics (which depend on the amount of silicic acid and its state) and physicochemical properties - the ability to act as a substrate during crystal formation. The proposed method can also be extended to other binding substances and materials. This article contributes to the understanding of the processes that occur during the structure formation of composites, which will make it possible to control the structure formation in the future, obtaining materials with a given set of properties.

The Nature of S-N Bonding in Sulfonamides and Related Compounds: Insights into π-Bonding Contributions from Sulfur K-Edge XAS

2020 ◽  
Author(s):  
Tulin Okbinoglu ◽  
Pierre Kennepohl
Keyword(s):  
Density Functional ◽  
Chemical Properties ◽  
Functional Theory ◽  
Rotational Barriers ◽  
Td Dft ◽  
Nitrogen Bonds ◽  
X Ray Absorption ◽  
Related Compounds ◽  
And Chemical Properties

Molecules containing sulfur-nitrogen bonds, like sulfonamides, have long been of interest due to their many uses and chemical properties. Understanding the factors that cause sulfonamide reactivity is important, yet their continues to be controversy regarding the relevance of S-N π bonding in describing these species. In this paper, we use sulfur K-edge x-ray absorption spectroscopy (XAS) in conjunction with density functional theory (DFT) to explore the role of S<sub>3p</sub> contributions to π-bonding in sulfonamides, sulfinamides and sulfenamides. We explore the nature of electron distribution of the sulfur atom and its nearest neighbors and extend the scope to explore the effects on rotational barriers along the sulfur-nitrogen axis. The experimental XAS data together with TD-DFT calculations confirm that sulfonamides, and the other sulfinated amides in this series, have essentially no S-N π bonding involving S<sub>3p</sub> contributions and that electron repulsion and is the dominant force that affect rotational barriers.

scholarly journals Strategies to Build Hybrid Protein–DNA Nanostructures

Nanomaterials ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 1332
Author(s):  
Armando Hernandez-Garcia
Keyword(s):  
Dynamic Systems ◽  
Dna Nanotechnology ◽  
Chemical Properties ◽  
Hybrid Nanostructures ◽  
Advanced Materials ◽  
Dna Nanostructures ◽  
Hybrid Protein ◽  
Structural Protein ◽  
The Individual ◽  
Structural Dna Nanotechnology

Proteins and DNA exhibit key physical chemical properties that make them advantageous for building nanostructures with outstanding features. Both DNA and protein nanotechnology have growth notably and proved to be fertile disciplines. The combination of both types of nanotechnologies is helpful to overcome the individual weaknesses and limitations of each one, paving the way for the continuing diversification of structural nanotechnologies. Recent studies have implemented a synergistic combination of both biomolecules to assemble unique and sophisticate protein–DNA nanostructures. These hybrid nanostructures are highly programmable and display remarkable features that create new opportunities to build on the nanoscale. This review focuses on the strategies deployed to create hybrid protein–DNA nanostructures. Here, we discuss strategies such as polymerization, spatial directing and organizing, coating, and rigidizing or folding DNA into particular shapes or moving parts. The enrichment of structural DNA nanotechnology by incorporating protein nanotechnology has been clearly demonstrated and still shows a large potential to create useful and advanced materials with cell-like properties or dynamic systems. It can be expected that structural protein–DNA nanotechnology will open new avenues in the fabrication of nanoassemblies with unique functional applications and enrich the toolbox of bionanotechnology.

scholarly journals Occurrence of drug target residues within decantation tank sediments: a good clue to assess their historical excretion?

2021 ◽  
Vol 31 (1) ◽  
Author(s):  
Thomas Thiebault ◽  
Laëtitia Fougère ◽  
Anaëlle Simonneau ◽  
Emilie Destandau ◽  
Claude Le Milbeau ◽  
...  
Keyword(s):  
Drug Target ◽  
Chemical Properties ◽  
Deposition Process ◽  
Drug Consumption ◽  
Organic Layers ◽  
Sewer Systems ◽  
Physico Chemical ◽  
Deep Underground ◽  
Deposition Processes

AbstractThis study investigated the potential of sediments accumulated in sewer systems to record human activities through the occurrence of drug target residues (DTR). The installation studied is 17 m deep underground decantation tank that traps the coarse fractions of a unitary sewer system (northern part of Orléans, France), collecting both stormwater and wastewater. The sediments deposited in this tank could constitute a nonesuch opportunity to study the historical evolution of illicit and licit drug consumption in the catchment, however, the deposition processes and the record of DTRs remain largely unknown at present. Five cores were acquired from 2015 to 2017. One hundred fifty-two sediment samples were extracted using a mixture of ultra-pure water:methanol (1:1) prior to analysis of the extracts by high-pressure liquid chromatography coupled to tandem mass spectrometry. Several classical sedimentological analyses such as total organic carbon, facies description and granulometry were also performed on these samples, in order to understand the most important factors (e.g., physico-chemical properties of the DTRs, solid type, assumed load in wastewater) impacting their deposition.The key role of the speciation of DTRs was highlighted by the higher contents in neutral and anionic DTRs in organic layers, whereas only cationic DTRs were found in mineral layers. The considerable modifications in the sediments’ properties, generated by distinct origins (i.e., stormwater or wastewater), are therefore the most important drivers that must be taken into account when back-calculating the historical patterns of drug consumption from their DTR concentrations in decantation tank sediments. Further research remains necessary to fully understand the deposition process, but this study provides new clues explaining these temporal evolutions.

scholarly journals Comprehensive Virtual Screening of the Antiviral Potentialities of Marine Polycyclic Guanidine Alkaloids against SARS-CoV-2 (COVID-19)

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 460
Author(s):  
Amr El-Demerdash ◽  
Ahmed M. Metwaly ◽  
Afnan Hassan ◽  
Tarek Mohamed Abd El-Aziz ◽  
Eslam B. Elkaeed ◽  
...  
Keyword(s):  
In Silico ◽  
Active Sites ◽  
Specific Treatment ◽  
Aqueous Solubility ◽  
Maximum Tolerated Dose ◽  
Binding Energies ◽  
Log P ◽  
Binding Affinities ◽  
Structural Protein ◽  
Guanidine Alkaloids

The huge global expansion of the COVID-19 pandemic caused by the novel SARS-corona virus-2 is an extraordinary public health emergency. The unavailability of specific treatment against SARS-CoV-2 infection necessitates the focus of all scientists in this direction. The reported antiviral activities of guanidine alkaloids encouraged us to run a comprehensive in silico binding affinity of fifteen guanidine alkaloids against five different proteins of SARS-CoV-2, which we investigated. The investigated proteins are COVID-19 main protease (Mpro) (PDB ID: 6lu7), spike glycoprotein (PDB ID: 6VYB), nucleocapsid phosphoprotein (PDB ID: 6VYO), membrane glycoprotein (PDB ID: 6M17), and a non-structural protein (nsp10) (PDB ID: 6W4H). The binding energies for all tested compounds indicated promising binding affinities. A noticeable superiority for the pentacyclic alkaloids particularly, crambescidin 786 (5) and crambescidin 826 (13) has been observed. Compound 5 exhibited very good binding affinities against Mpro (ΔG = −8.05 kcal/mol), nucleocapsid phosphoprotein (ΔG = −6.49 kcal/mol), and nsp10 (ΔG = −9.06 kcal/mol). Compound 13 showed promising binding affinities against Mpro (ΔG = −7.99 kcal/mol), spike glycoproteins (ΔG = −6.95 kcal/mol), and nucleocapsid phosphoprotein (ΔG = −8.01 kcal/mol). Such promising activities might be attributed to the long ω-fatty acid chain, which may play a vital role in binding within the active sites. The correlation of c Log P with free binding energies has been calculated. Furthermore, the SAR of the active compounds has been clarified. The Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) studies were carried out in silico for the 15 compounds; most examined compounds showed optimal to good range levels of ADMET aqueous solubility, intestinal absorption and being unable to pass blood brain barrier (BBB), non-inhibitors of CYP2D6, non-hepatotoxic, and bind plasma protein with a percentage less than 90%. The toxicity of the tested compounds was screened in silico against five models (FDA rodent carcinogenicity, carcinogenic potency TD50, rat maximum tolerated dose, rat oral LD50, and rat chronic lowest observed adverse effect level (LOAEL)). All compounds showed expected low toxicity against the tested models. Molecular dynamic (MD) simulations were also carried out to confirm the stable binding interactions of the most promising compounds, 5 and 13, with their targets. In conclusion, the examined 15 alkaloids specially 5 and 13 showed promising docking, ADMET, toxicity and MD results which open the door for further investigations for them against SARS-CoV-2.

The Role of Gait Analysis in Clinical Medicine: A Survey of UK Centres

1987 ◽  
Vol 16 (4) ◽  
pp. 221-227 ◽  
Author(s):  
N Messenger ◽  
P Bowker
Keyword(s):  
Gait Analysis ◽  
Clinical Medicine ◽  
Final Analysis ◽  
Clinical Work ◽  
Clinical Context ◽  
Clinical Value ◽  
Analysis Techniques ◽  
Subjective Views ◽  
The Uk

This paper reports the results of a survey carried out to assess the clinical usage currently being made of gait analysis facilities within the UK. Thirty-five centres were circulated with a questionnaire which requested information under four main headings: (i) equipment, (ii) research projects, (iii) clinical service commitments, and (iv) subjective views of the ultimate clinical value of the service. Of the 25 completed questionnaires returned, 16 were suitable for inclusion in the final analysis of data. The survey provided useful data on the equipment and facilities available in each centre together with details of the service available to prospective referring clinicians. Ten centres were considered as being currently involved in some clinical work, with six of these being routinely involved. The respondents generally felt that gait analysis techniques have a clinical context, if not yet routinely, but the numbers of referrals to the centres is still quite small. A number of areas worthy of further work were identified by the respondents. It is hoped that presentation of these results will stimulate dialogue between centres and between clinicians and bioengineers.

scholarly journals Identification of Tyr residues that enhance folate substrate binding and constrain oscillation of the proton-coupled folate transporter (PCFT-SLC46A1)

2015 ◽  
Vol 308 (8) ◽  
pp. C631-C641 ◽  
Author(s):  
Michele Visentin ◽  
Ersin Selcuk Unal ◽  
Mitra Najmi ◽  
Andras Fiser ◽  
Rongbao Zhao ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Rate Constant ◽  
Binding Pocket ◽  
Wild Type ◽  
Efflux Rate ◽  
High Affinity ◽  
Extracellular Compartment ◽  
Efflux Rate Constant ◽  
Opposite Compartment

The proton-coupled folate transporter (PCFT) mediates intestinal folate absorption and transport of folates across the choroid plexus. This study focuses on the role of Tyr residues in PCFT function. The substituted Cys-accessibility method identified four Tyr residues (Y291, Y362, Y315, and Y414) that are accessible to the extracellular compartment; three of these (Y291, Y362, and Y315) are located within or near the folate binding pocket. When the Tyr residues were replaced with Cys or Ala, these mutants showed similar (up to 6-fold) increases in influx Vmax and Kt/ Ki for [3H]methotrexate and [3H]pemetrexed. When the Tyr residues were replaced with Phe, these changes were moderated or absent. When Y315A PCFT was used as representative of the mutants and [3H]pemetrexed as the transport substrate, this substitution did not increase the efflux rate constant. Furthermore, neither influx nor efflux mediated by Y315A PCFT was transstimulated by the presence of substrate in the opposite compartment; however, substantial bidirectional transstimulation of transport was mediated by wild-type PCFT. This resulted in a threefold greater efflux rate constant for cells that express wild-type PCFT than for cells that express Y315 PCFT under exchange conditions. These data suggest that these Tyr residues, possibly through their rigid side chains, secure the carrier in a high-affinity state for its folate substrates. However, this may be achieved at the expense of constraining the carrier's mobility, thereby decreasing the rate at which the protein oscillates between its conformational states. The Vmax generated by these Tyr mutants may be so rapid that further augmentation during transstimulation may not be possible.

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