scholarly journals Plasticity of the 340-Loop in Influenza Neuraminidase Offers New Insight for Antiviral Drug Development

2020 ◽  
Vol 21 (16) ◽  
pp. 5655
Author(s):  
Nanyu Han ◽  
Justin Tze Yang Ng ◽  
Yanpeng Li ◽  
Yuguang Mu ◽  
Zunxi Huang
Keyword(s):  
Antiviral Drug ◽  
Dynamics Simulation ◽  
Side Chain ◽  
Structure Based Drug Design ◽  
Sialic Acid Binding ◽  
The Stability ◽  
First Time ◽  
Side Chain Orientation ◽  
Simulation Time

The recently discovered 340-cavity in influenza neuraminidase (NA) N6 and N7 subtypes has introduced new possibilities for rational structure-based drug design. However, the plasticity of the 340-loop (residues 342–347) and the role of the 340-loop in NA activity and substrate binding have not been deeply exploited. Here, we investigate the mechanism of 340-cavity formation and demonstrate for the first time that seven of nine NA subtypes are able to adopt an open 340-cavity over 1.8 μs total molecular dynamics simulation time. The finding that the 340-loop plays a role in the sialic acid binding pathway suggests that the 340-cavity can function as a druggable pocket. Comparing the open and closed conformations of the 340-loop, the side chain orientation of residue 344 was found to govern the formation of the 340-cavity. Additionally, the conserved calcium ion was found to substantially influence the stability of the 340-loop. Our study provides dynamical evidence supporting the 340-cavity as a druggable hotspot at the atomic level and offers new structural insight in designing antiviral drugs.

scholarly journals Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling

2020 ◽  
Vol 6 (37) ◽  
pp. eabb8368 ◽  
Author(s):  
Hemlata Dwivedi-Agnihotri ◽  
Madhu Chaturvedi ◽  
Mithu Baidya ◽  
Tomasz Maciej Stepniewski ◽  
Shubhi Pandey ◽  
...  
Keyword(s):  
G Protein ◽  
Phosphorylation Site ◽  
Dynamics Simulation ◽  
Phosphorylation Sites ◽  
Functional Responses ◽  
Biased Signaling ◽  
The Stability ◽  
G Protein Coupled ◽  
Structural Aspects

Agonist-induced phosphorylation of G protein–coupled receptors (GPCRs) is a key determinant for their interaction with β-arrestins (βarrs) and subsequent functional responses. Therefore, it is important to decipher the contribution and interplay of different receptor phosphorylation sites in governing βarr interaction and functional outcomes. Here, we find that several phosphorylation sites in the human vasopressin receptor (V2R), positioned either individually or in clusters, differentially contribute to βarr recruitment, trafficking, and ERK1/2 activation. Even a single phosphorylation site in V2R, suitably positioned to cross-talk with a key residue in βarrs, has a decisive contribution in βarr recruitment, and its mutation results in strong G-protein bias. Molecular dynamics simulation provides mechanistic insights into the pivotal role of this key phosphorylation site in governing the stability of βarr interaction and regulating the interdomain rotation in βarrs. Our findings uncover important structural aspects to better understand the framework of GPCR-βarr interaction and biased signaling.

PHOTOACOUSTIC MEASUREMENT AND MOLECULAR DYNAMICS SIMULATION FOR THERMAL CONDUCTIVITY OF Al0.3Ga0.7As

2003 ◽  
Vol 14 (01) ◽  
pp. 61-72 ◽  
Author(s):  
S. CHITRA ◽  
A. JALAL ◽  
K. RAMACHANDRAN ◽  
S. RAJAGOPAL
Keyword(s):  
Thermal Conductivity ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Thermal Property ◽  
Dynamics Simulation ◽  
Experimental Setup ◽  
Photoacoustic Technique ◽  
Photoacoustic Measurement ◽  
First Time

The thermal conductivity of Al 0.3 Ga 0.7 As is studied using photoacoustic technique and molecular dynamics simulation. Tersoff's potential is used for the simulation, for the first time, to this alloy. Thermal conductivity, determined experimentally by photoacoustic technique using our experimental setup, agrees well with the molecular dynamics simulation and literature values. The results are compared with the host GaAs and the role of DX centers in thermal property is discussed.

scholarly journals Revealing the unknown aspects of initial steps of prenylated flavin mononucleotide biosynthesis – the role of Lys129 in PaUbiX

2021 ◽  
Author(s):  
Szymon Zaczek ◽  
Agnieszka Dybala-Defratyka
Keyword(s):  
Active Sites ◽  
Laboratory Experiments ◽  
Phosphate Group ◽  
Flavin Mononucleotide ◽  
Dipolar Cycloaddition ◽  
Quantum Mechanical ◽  
Constant Ph ◽  
First Time ◽  
Simulation Time

Background Prenylated flavin mononucleotide (prFMN) is a recently discovered, heavily modified flavin compound. It is the only known cofactor that enables enzymatic 1,3-dipolar cycloaddition reactions. It is produced by enzymes from UbiX family, from flavin mononucleotide and either dimethylallyl mono- or diphosphate. prFMN biosynthesis is currently reported to be initiated by a protonation of the substrate by Glu140. Methods Computational chemistry methods are applied herein - mostly different flavors of molecular dynamics MD, such as Constant pH MD, hybrid Quantum-Mechanical / Molecular Mechanical MD, and classical MD. Results Glu140 competes for a single proton with Lys129 but it is the latter that adopted a protonated state throughout most of the simulation time. Lys129 plays a key role in the positioning of the DMAP’s phosphate group within the PaUbiX active site. DMAP’s breakdown into a phosphate and a prenyl group can be decoupled from the protona-tion of the DMAP’s phosphate group. Conclusions The role of Lys129 in functioning of PaUbiX is reported for the first time. The severity of interactions between Glu140, Lys129, and DMAP’s phosphate group enables an unusual decoupling of phosphate’s protonation from DMAP’s breakdown. Those findings are most likely conserved throughout the UbiX family to the structural re-semblence of active sites of those proteins. Significance Mechanistic insights into a crucial biochemical process, biosynthesis of prFMN, are provided. This study, alt-hough purely computational, extends and perfectly complements the knowledge obtained in classical laboratory experiments.

scholarly journals Comparative analysis of the unbinding pathways of antiviral drug Indinavir from HIV and HTLV1 proteases by Supervised Molecular Dynamics simulation

2021 ◽  
Author(s):  
Farzin Sohraby ◽  
Hassan Aryapour
Keyword(s):  
Inhibitory Activity ◽  
Antiviral Drug ◽  
Good Explanation ◽  
Dynamics Simulation ◽  
Stacking Interactions ◽  
Pi Stacking ◽  
Efficacious Treatment ◽  
The Stability ◽  
Flap Region ◽  
Hiv 1

Determining the unbinding pathways of potential small molecule compounds from their target proteins is of great significance for designing efficacious treatment solutions. One of these potential compounds is the approved HIV-1 protease inhibitor, indinavir, which has a weak effect on the HTLV-1 protease. In this work, by employing SuMD method, we reconstructed the unbinding pathways of indinavir from HIV and HTLV-1 proteases in order to compare and to understand the mechanism of the unbinding, and also to discover the reasons for the lack of inhibitory activity of indinavir against the HTLV-1 protease. We achieved multiple unbinding events from both HIV and HTLV-1 proteases in which the RMSD values of indinavir reached over 4 nm. Also, we found that the mobility and the fluctuations of the flap region is higher in the HTLV-1 protease which makes the drug less stable. We realized that critically positioned aromatic residues such as Trp98/Trp98' and Phe67/Phe67' in the HTLV-1 protease can make strong pi-Stacking interactions with indinavir in the unbinding pathway which are unfavorable for the stability of indinavir in the active site. The details found in this study can make a good explanation for the lack of inhibitory activity of this drug against HTLV-1 protease. We believe the details discovered in this work can be a great assist for designing more effective and more selective inhibitors for the HTLV-1 protease.

scholarly journals Lignocaine’s substantial role in COVID-19 management: potential remedial and therapeutic implications

2020 ◽  
Vol 24 (1) ◽  
pp. 59-63
Author(s):  
Nasser Ali Malik ◽  
Amjid Hammodi ◽  
Dayanidhi Ramachandra Jaiswara
Keyword(s):  
Ion Channel ◽  
Antiviral Drug ◽  
Respiratory Illness ◽  
Health Concern ◽  
Therapeutic Implications ◽  
Substantial Role ◽  
Anti Inflammatory ◽  
Ion Channel Blocking ◽  
First Time

Background: The outbreak caused by SARS CoV-2 of the recent coronavirus disease-2019 (COVID-19) has been marked as a public health concern with a significant mortality at the global level. Lignocaine a common anesthetic agent being used for pain free surgeries for over a long period of time has expressed extensive characteristic of being an anti-inflammatory, antibacterial, direct spasmolytic,  ion channel blocking and repolarization agent. We did a literature review Methodology: Currently compiled over-view has for the first time evaluated the probable curative and therapeutic role of nebulized lignocaine drug against SARS CoV-2 by utilization of PubMed, MEDLINE, NHS Evidence and Web of Science databases. Results: With evidence of nebulized lignocaine being used successfully in respiratory illness before and the established role of low concentration lignocaine as ion channel repolarization agent, we try to interpret and deduce the possible implication of nebulized lignocaine as possible therapeutic agent and a potential cure against SARS-CoV-2 caused respiratory illness by acting as an anti-inflammatory agent during SARS-CoV-2 caused acute lung injury and also possibly as an antiviral drug.  Conclusion: By the virtue of possessing anti-inflammatory effect and potential antiviral effects, nebulized lignocaine can be a breakthrough in the management of the current COVID-19 pandemic.     Citation: Malik NA, Lignocaine’s substantial role in COVID-19 management: potential remedial and therapeutic implications. Anaesth. pain & intensive care 2019;23(1):84-91 Received: 29 March 2020; Reviewed & Accepted: 5 April 2020;

Stabilisation of Aragonite: The Role of Mg2+ and Other Impurity Ions

2019 ◽  
Author(s):  
Matthew Boon ◽  
William Rickard ◽  
Andrew Rohl ◽  
Franca Jones
Keyword(s):  
Electron Backscatter Diffraction ◽  
Crystal Formation ◽  
Sulfate Ions ◽  
Inorganic Systems ◽  
Sodium Magnesium ◽  
Stable Product ◽  
The Stability ◽  
Backscatter Diffraction ◽  
First Time

Aragonite formation and stabilisation in seawater is still an area of active investigation since the thermodynamically stable product at room temperature is calcite. In this manuscript, purely inorganic systems that were found to stabilise aragonite were analysed by various techniques. Dynamic Light Scattering was used to characterise the nucleation behaviour of the system and it was found that the presence of magnesium ions during crystal formation inhibits nucleation overall, not just calcite nucleation. In addition, it was found that sulfate is not necessary to stabilise aragonite. Microanalysis by energy dispersive X-ray spectroscopy (EDS) and electron backscatter diffraction (EBSD) revealed that the aragonite that was formed had a disordered core with, sodium, magnesium and sulfate ions incorporated into the structure. To the best of the authors’ knowledge this is the first time an ACC core in aragonite has been visualised in a completely abiotic, synthetic system (in the absence of organic molecules). Inclusion of these impurities into the structure may explain the stability of aragonite in natural seawaters.

Homology Modeling and Evaluation of Sars-Cov-2 Spike Protein Mutant

2021 ◽  
Vol 6 (4) ◽  
pp. 38-55
Author(s):  
Hima Vyshnavi ◽  
Aswin Mohan ◽  
Shahanas Naisam ◽  
Suvanish Kumar ◽  
Nidhin Sreekumar
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Antiviral Drug ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Structure Modeling ◽  
Ramachandran Plot ◽  
Global Pandemic ◽  
The Stability

Severe acute respiratory syndrome coronavirus 2 (SARS‐Cov-2), a global pandemic, affected the world, increasing every day. A mutated variant D614G, showing more virulence and transmission, was studied for forecasting the emergence of more virulent and pathogenic viral strains. This study focuses on structure modeling and validation. Characterization of proteins homologous to wild spike protein was done, and homology models of the mutated variant were modeled using these proteins. Validation of models was done using Ramachandran plot and ERRAT plot. Molecular dynamics simulation was used to validate the stability of the models, and binding affinity of these models were estimated by molecular docking with an approved antiviral drug. Docked complexes were studied and the best model was selected. Molecular dynamics simulation was used to estimate the stability of the docked complex. The model of 6VXX, a homologous of wild spike protein, was found to be stable with the interaction of the antiviral drug from this study.

Virtual screening assisted identification of small molecule against 2019 novel coronavirus protease enzyme

2020 ◽  
Vol 7 ◽  
Author(s):  
Arkadeep Sarkar ◽  
Deepak Shilkar ◽  
Arindam Maity ◽  
Sarmi Sardar ◽  
Sudhan Debnath ◽  
...  
Keyword(s):  
Essential Amino Acids ◽  
Dynamics Simulation ◽  
Design Studies ◽  
Structure Based Drug Design ◽  
Protease Enzyme ◽  
Main Protease ◽  
Coronavirus Infection ◽  
The Stability ◽  
Novel Coronavirus ◽  
Global Threat

The 2019 novel coronavirus infection or COVID-19 can be designated as a global threat. Till date, there is a lack of dedicated therapeutics available against this fatal infection. In the present work, we performed structure-based drug design studies in order to identify clinically used molecules exhibiting crucial binding with 2019-coronavirus main protease enzyme. Based on ligand binding energy and interaction with essential amino acids, two molecules were selected. The stability of the complexed molecules with main protease enzyme was further studied by performing molecular dynamics simulation.

First evidence of formation of stable DBU Zn-phthalocyanine complexes: synthesis and characterization

2005 ◽  
Vol 09 (07) ◽  
pp. 519-527 ◽  
Author(s):  
Roberta Del Sole ◽  
Agnese De Luca ◽  
Giuseppe Mele ◽  
Giuseppe Vasapollo
Keyword(s):  
Thermal Analysis ◽  
Axial Ligand ◽  
Synthesis And Characterization ◽  
One Pot ◽  
Strong Base ◽  
Pyridine Complex ◽  
The Stability ◽  
First Time ◽  
Complex Thermal Analysis

Novel Zn (II) phthalocyanine and naphthalocyanine DBU complexes have been prepared in a one-pot synthesis reacting phthalonitrile precursors with an excess of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). For the first time, it has been well evidenced that DBU played the role of coordinating axial ligand together with the well known role of strong base. Also, DBU complexes showed better solubility in organic solvents due to the coordination of the bulky axial DBU ligand, compared to the Zn (II) phthalocyanines and naphthalocyanines without coordinated DBU. The coordinating properties of DBU toward ZnPcs (DBU free) complexes have also been investigated along with the ZnPc (pyridine) complex. Thermal analysis results reflecting the stability of the synthesized complexes under air are also presented.

Side chain engineering of organic sensitizers for dye-sensitized solar cells: a strategy to improve performances and stability

2017 ◽  
Vol 5 (13) ◽  
pp. 6122-6130 ◽  
Author(s):  
Damien Joly ◽  
Maxime Godfroy ◽  
Laia Pellejà ◽  
Yann Kervella ◽  
Pascale Maldivi ◽  
...  
Keyword(s):  
Solar Cells ◽  
Dye Sensitized Solar Cells ◽  
Side Chain ◽  
Photovoltaic Devices ◽  
Dye Sensitized ◽  
The Stability ◽  
Sensitized Solar Cells ◽  
Organic Sensitizers

We unraveled the role of alkyl substituents, usually employed as solubilizing groups for organic sensitizers, in the performances and the stability of photovoltaic devices.

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