In silico modeling of aspalathin and nothofagin against SGLT2

The homology model of hSGLT2 (human sodium dependent glucose co-transporter 2) was used as a target for diabetes mellitus. Molecular docking and dynamics simulations were carried out on vitexin- and isovitexin-SGLT2 complexes with dapagliflozin as positive control. The results show that both vitexin and isovitexin have weaker binding energies compared to dapagliflozin, indicating that both ligands may exhibit weak anti-diabetic effects through inhibiting SGLT2. The poor binding mode of vitexin and isovitexin may be responsible for their weak anti-diabetic effect. These results are in accordance with the inhibitory activity against hSGLT2 in vitro test with the inhibitory rate 26.3% of vitexin and 11.2% of isovitexin at the dose of 10[Formula: see text][Formula: see text]mol[Formula: see text][Formula: see text][Formula: see text]L[Formula: see text]. The results of calculation and in vitro test may explain the possible inhibiting mechanism of vitexin and isovitexin against SGLT2, and therefore enhance our understanding of the structure-activity relationships of SGLT2 inhibitors.

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On the Adsorption of Aspartate Derivatives to Calcite Surfaces in Aqueous Environment

10.26434/chemrxiv.11558430.v1 ◽

2020 ◽

Author(s):

Robert Stepic ◽

Lara Jurković ◽

Ksenia Klementyeva ◽

Marko Ukrainczyk ◽

Matija Gredičak ◽

...

Keyword(s):

Active Sites ◽

Realistic Model ◽

Binding Energies ◽

Inhibition Mechanism ◽

Aqueous Environment ◽

Binding Modes ◽

Carboxylate Groups ◽

Dissolved Ions ◽

Living Organisms ◽

Dynamics Simulations

In many living organisms, biomolecules interact favorably with various surfaces of calcium carbonate. In this work, we have considered the interactions of aspartate (Asp) derivatives, as models of complex biomolecules, with calcite. Using kinetic growth experiments, we have investigated the inhibition of calcite growth by Asp, Asp2 and Asp3.This entailed the determination of a step-pinning growth regime as well as the evaluation of the adsorption constants and binding free energies for the three species to calcite crystals. These latter values are compared to free energy profiles obtained from fully atomistic molecular dynamics simulations. When using a flat (104) calcite surface in the models, the measured trend of binding energies is poorly reproduced. However, a more realistic model comprised of a surface with an island containing edges and corners, yields binding energies that compare very well with experiments. Surprisingly, we find that most binding modes involve the positively charged, ammonium group. Moreover, while attachment of the negatively charged carboxylate groups is also frequently observed, it is always balanced by the aqueous solvation of an equal or greater number of carboxylates. These effects are observed on all calcite features including edges and corners, the latter being associated with dominant affinities to Asp derivatives. As these features are also precisely the active sites for crystal growth, the experimental and theoretical results point strongly to a growth inhibition mechanism whereby these sites become blocked, preventing further attachment of dissolved ions and halting further growth.

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A Novel Integrated Way for Deciphering the Glycan Code for the FimH Lectin

Molecules ◽

10.3390/molecules23112794 ◽

2018 ◽

Vol 23 (11) ◽

pp. 2794 ◽

Cited By ~ 2

Author(s):

Tetiana Dumych ◽

Clarisse Bridot ◽

Sébastien Gouin ◽

Marc Lensink ◽

Solomiya Paryzhak ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Bacterial Adhesion ◽

Binding Energies ◽

Conformational Space ◽

Binding Modes ◽

E Coli ◽

Binding Enthalpy ◽

Dynamics Simulations ◽

Adhesion And Invasion

The fimbrial lectin FimH from uro- and enteropathogenic Escherichia coli binds with nanomolar affinity to oligomannose glycans exposing Manα1,3Man dimannosides at their non-reducing end, but only with micromolar affinities to Manα1,2Man dimannosides. These two dimannoses play a significantly distinct role in infection by E. coli. Manα1,2Man has been described early on as shielding the (Manα1,3Man) glycan that is more relevant to strong bacterial adhesion and invasion. We quantified the binding of the two dimannoses (Manα1,2Man and Manα1,3Man to FimH using ELLSA and isothermal microcalorimetry and calculated probabilities of binding modes using molecular dynamics simulations. Our experimentally and computationally determined binding energies confirm a higher affinity of FimH towards the dimannose Manα1,3Man. Manα1,2Man displays a much lower binding enthalpy combined with a high entropic gain. Most remarkably, our molecular dynamics simulations indicate that Manα1,2Man cannot easily take its major conformer from water into the FimH binding site and that FimH is interacting with two very different conformers of Manα1,2Man that occupy 42% and 28% respectively of conformational space. The finding that Manα1,2Man binding to FimH is unstable agrees with the earlier suggestion that E. coli may use the Manα1,2Man epitope for transient tethering along cell surfaces in order to enhance dispersion of the infection.

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On the Adsorption of Aspartate Derivatives to Calcite Surfaces in Aqueous Environment

10.26434/chemrxiv.11558430 ◽

2020 ◽

Author(s):

Robert Stepic ◽

Lara Jurković ◽

Ksenia Klementyeva ◽

Marko Ukrainczyk ◽

Matija Gredičak ◽

...

Keyword(s):

Active Sites ◽

Realistic Model ◽

Binding Energies ◽

Inhibition Mechanism ◽

Aqueous Environment ◽

Binding Modes ◽

Carboxylate Groups ◽

Dissolved Ions ◽

Living Organisms ◽

Dynamics Simulations

In many living organisms, biomolecules interact favorably with various surfaces of calcium carbonate. In this work, we have considered the interactions of aspartate (Asp) derivatives, as models of complex biomolecules, with calcite. Using kinetic growth experiments, we have investigated the inhibition of calcite growth by Asp, Asp2 and Asp3.This entailed the determination of a step-pinning growth regime as well as the evaluation of the adsorption constants and binding free energies for the three species to calcite crystals. These latter values are compared to free energy profiles obtained from fully atomistic molecular dynamics simulations. When using a flat (104) calcite surface in the models, the measured trend of binding energies is poorly reproduced. However, a more realistic model comprised of a surface with an island containing edges and corners, yields binding energies that compare very well with experiments. Surprisingly, we find that most binding modes involve the positively charged, ammonium group. Moreover, while attachment of the negatively charged carboxylate groups is also frequently observed, it is always balanced by the aqueous solvation of an equal or greater number of carboxylates. These effects are observed on all calcite features including edges and corners, the latter being associated with dominant affinities to Asp derivatives. As these features are also precisely the active sites for crystal growth, the experimental and theoretical results point strongly to a growth inhibition mechanism whereby these sites become blocked, preventing further attachment of dissolved ions and halting further growth.

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Potential Inhibitors for Novel Coronavirus Protease Identified by Virtual Screening of 606 Million Compounds

International Journal of Molecular Sciences ◽

10.3390/ijms21103626 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3626 ◽

Cited By ~ 28

Author(s):

André Fischer ◽

Manuel Sellner ◽

Santhosh Neranjan ◽

Martin Smieško ◽

Markus A. Lill

Keyword(s):

Viral Infections ◽

Chemical Space ◽

Drug Repurposing ◽

Close Relation ◽

Binding Energies ◽

Proteolytic Processing ◽

Binding Modes ◽

Novel Coronavirus ◽

Dynamics Simulations ◽

Potential Inhibitors

The rapid outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China followed by its spread around the world poses a serious global concern for public health. To this date, no specific drugs or vaccines are available to treat SARS-CoV-2 despite its close relation to the SARS-CoV virus that caused a similar epidemic in 2003. Thus, there remains an urgent need for the identification and development of specific antiviral therapeutics against SARS-CoV-2. To conquer viral infections, the inhibition of proteases essential for proteolytic processing of viral polyproteins is a conventional therapeutic strategy. In order to find novel inhibitors, we computationally screened a compound library of over 606 million compounds for binding at the recently solved crystal structure of the main protease (Mpro) of SARS-CoV-2. A screening of such a vast chemical space for SARS-CoV-2 Mpro inhibitors has not been reported before. After shape screening, two docking protocols were applied followed by the determination of molecular descriptors relevant for pharmacokinetics to narrow down the number of initial hits. Next, molecular dynamics simulations were conducted to validate the stability of docked binding modes and comprehensively quantify ligand binding energies. After evaluation of potential off-target binding, we report a list of 12 purchasable compounds, with binding affinity to the target protease that is predicted to be more favorable than that of the cocrystallized peptidomimetic compound. In order to quickly advise ongoing therapeutic intervention for patients, we evaluated approved antiviral drugs and other protease inhibitors to provide a list of nine compounds for drug repurposing. Furthermore, we identified the natural compounds (−)-taxifolin and rhamnetin as potential inhibitors of Mpro. Rhamnetin is already commercially available in pharmacies.

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Inhibitors for Novel Coronavirus Protease Identified by Virtual Screening of 687 Million Compounds

10.26434/chemrxiv.11923239.v1 ◽

2020 ◽

Cited By ~ 7

Author(s):

André Fischer ◽

Manuel Sellner ◽

Santhosh Neranjan ◽

Markus A. Lill ◽

Martin Smieško

Keyword(s):

Viral Infections ◽

Chemical Space ◽

Binding Free Energy ◽

Close Relation ◽

Binding Energies ◽

Proteolytic Processing ◽

Binding Modes ◽

Compound Library ◽

Novel Coronavirus ◽

Dynamics Simulations

The rapid outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China followed by its spread around the world poses a serious global concern for public health with almost 90000 people infected and thousands of fatalities. To conquer viral infections, the inhibition of proteases essential for proteolytic processing of viral polyproteins is a conventional therapeutic strategy. To this date, no specific drugs or vaccines are available to treat SARS-CoV-2 despite its close relation to the SARS-CoV-1 virus that caused a similar epidemic in 2003. Thus, there remains an urgent need for the development of specific antiviral therapeutics to conquer SARS-CoV-2. In order to find novel inhibitors, we computationally screened a compound library of over 687 million compounds for binding at the recently solved crystal structure of the main protease of SARS-CoV-2. A screening of such a vast chemical space for SARS-CoV-2 protease inhibitors has not been reported before. After shape screening, two docking protocols were applied followed by the determination of pharmacokinetically relevant molecular descriptors to narrow down the initial hits. Next, molecular dynamics simulations were conducted to validate the stability of docked binding modes and comprehensively quantify ligand binding energies. After evaluation of off-target binding, we report a list of 11 drug-like compounds with improved binding free energy to the target protease in contrast to the cocrystallized peptidomimetic lead compound that suffers from poor pharmacokinetic properties. Furthermore, we identified one potent binder with comparable properties from the natural compound library.

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Potential Inhibitors for Novel Coronavirus Protease Identified by Virtual Screening of 606 Million Compounds

10.26434/chemrxiv.11923239.v2 ◽

2020 ◽

Author(s):

André Fischer ◽

Manuel Sellner ◽

Santhosh Neranjan ◽

Markus A. Lill ◽

Martin Smieško

Keyword(s):

Viral Infections ◽

Chemical Space ◽

Binding Free Energy ◽

Close Relation ◽

Binding Energies ◽

Proteolytic Processing ◽

Binding Modes ◽

Compound Library ◽

Novel Coronavirus ◽

Dynamics Simulations

The rapid outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China followed by its spread around the world poses a serious global concern for public health with almost 90000 people infected and thousands of fatalities. To conquer viral infections, the inhibition of proteases essential for proteolytic processing of viral polyproteins is a conventional therapeutic strategy. To this date, no specific drugs or vaccines are available to treat SARS-CoV-2 despite its close relation to the SARS-CoV-1 virus that caused a similar epidemic in 2003. Thus, there remains an urgent need for the development of specific antiviral therapeutics to conquer SARS-CoV-2. In order to find novel inhibitors, we computationally screened a compound library of over 687 million compounds for binding at the recently solved crystal structure of the main protease of SARS-CoV-2. A screening of such a vast chemical space for SARS-CoV-2 protease inhibitors has not been reported before. After shape screening, two docking protocols were applied followed by the determination of pharmacokinetically relevant molecular descriptors to narrow down the initial hits. Next, molecular dynamics simulations were conducted to validate the stability of docked binding modes and comprehensively quantify ligand binding energies. After evaluation of off-target binding, we report a list of 11 drug-like compounds with improved binding free energy to the target protease in contrast to the cocrystallized peptidomimetic lead compound that suffers from poor pharmacokinetic properties. Furthermore, we identified one potent binder with comparable properties from the natural compound library.

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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 ◽

10.3390/molecules26175230 ◽

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.

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Potential Inhibitors for Novel Coronavirus Protease Identified by Virtual Screening of 606 Million Compounds

10.26434/chemrxiv.11923239 ◽

2020 ◽

Cited By ~ 1

Author(s):

André Fischer ◽

Manuel Sellner ◽

Santhosh Neranjan ◽

Markus A. Lill ◽

Martin Smieško

Keyword(s):

Viral Infections ◽

Chemical Space ◽

Binding Free Energy ◽

Close Relation ◽

Binding Energies ◽

Proteolytic Processing ◽

Binding Modes ◽

Compound Library ◽

Novel Coronavirus ◽

Dynamics Simulations

The rapid outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China followed by its spread around the world poses a serious global concern for public health with almost 90000 people infected and thousands of fatalities. To conquer viral infections, the inhibition of proteases essential for proteolytic processing of viral polyproteins is a conventional therapeutic strategy. To this date, no specific drugs or vaccines are available to treat SARS-CoV-2 despite its close relation to the SARS-CoV-1 virus that caused a similar epidemic in 2003. Thus, there remains an urgent need for the development of specific antiviral therapeutics to conquer SARS-CoV-2. In order to find novel inhibitors, we computationally screened a compound library of over 687 million compounds for binding at the recently solved crystal structure of the main protease of SARS-CoV-2. A screening of such a vast chemical space for SARS-CoV-2 protease inhibitors has not been reported before. After shape screening, two docking protocols were applied followed by the determination of pharmacokinetically relevant molecular descriptors to narrow down the initial hits. Next, molecular dynamics simulations were conducted to validate the stability of docked binding modes and comprehensively quantify ligand binding energies. After evaluation of off-target binding, we report a list of 11 drug-like compounds with improved binding free energy to the target protease in contrast to the cocrystallized peptidomimetic lead compound that suffers from poor pharmacokinetic properties. Furthermore, we identified one potent binder with comparable properties from the natural compound library.

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Recent Advances of In-Silico Modeling of Potent Antagonists for the Adenosine Receptors

Current Pharmaceutical Design ◽

10.2174/1381612825666190304123545 ◽

2019 ◽

Vol 25 (7) ◽

pp. 750-773 ◽

Cited By ~ 11

Author(s):

Pabitra Narayan Samanta ◽

Supratik Kar ◽

Jerzy Leszczynski

Keyword(s):

Drug Targets ◽

Biological Activities ◽

Scoring Function ◽

Md Simulations ◽

Energy Calculation ◽

Binding Modes ◽

Macromolecular Systems ◽

In Silico Modeling ◽

Mathematical Algorithms ◽

The Impact

The rapid advancement of computer architectures and development of mathematical algorithms offer a unique opportunity to leverage the simulation of macromolecular systems at physiologically relevant timescales. Herein, we discuss the impact of diverse structure-based and ligand-based molecular modeling techniques in designing potent and selective antagonists against each adenosine receptor (AR) subtype that constitutes multitude of drug targets. The efficiency and robustness of high-throughput empirical scoring function-based approaches for hit discovery and lead optimization in the AR family are assessed with the help of illustrative examples that have led to nanomolar to sub-micromolar inhibition activities. Recent progress in computer-aided drug discovery through homology modeling, quantitative structure-activity relation, pharmacophore models, and molecular docking coupled with more accurate free energy calculation methods are reported and critically analyzed within the framework of structure-based virtual screening of AR antagonists. Later, the potency and applicability of integrated molecular dynamics (MD) methods are addressed in the context of diligent inspection of intricated AR-antagonist binding processes. MD simulations are exposed to be competent for studying the role of the membrane as well as the receptor flexibility toward the precise evaluation of the biological activities of antagonistbound AR complexes such as ligand binding modes, inhibition affinity, and associated thermodynamic and kinetic parameters.

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