Phototriggerable peptidomimetics for the inhibition of Mycobacterium tuberculosis ribonucleotide reductase by targeting protein–protein binding

2015 ◽  
Vol 13 (9) ◽  
pp. 2612-2621 ◽  
Author(s):  
Christoffer Karlsson ◽  
Magnus Blom ◽  
Miranda Johansson (neé Varedian) ◽  
Anna M. Jansson ◽  
Enzo Scifo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Protein Binding ◽  
Ribonucleotide Reductase ◽  
Subunit C ◽  
Peptidomimetic Inhibitors ◽  
R2 Subunit

Peptidomimetic inhibitors with photomodulable affinity for the R1–R2 subunit association site were designed based on the R2-subunit C-terminal.

scholarly journals Production of the R2 subunit of ribonucleotide reductase from herpes simplex virus with prokaryotic and eukaryotic expression systems: higher activity of R2 produced by eukaryotic cells related to higher iron-binding capacity

1996 ◽  
Vol 320 (1) ◽  
pp. 129-135 ◽  
Author(s):  
Nathalie LAMARCHE ◽  
Gilles MATTON ◽  
Bernard MASSIE ◽  
Marc FONTECAVE ◽  
Mohamed ATTA ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Ribonucleotide Reductase ◽  
Binding Capacity ◽  
Eukaryotic Expression ◽  
Eukaryotic Cells ◽  
Expression Systems ◽  
Simplex Virus ◽  
R2 Subunit ◽  
Eukaryotic Expression Systems

The R2 subunit of ribonucleotide reductase from herpes simplex virus type 2 was overproduced with prokaryotic and eukaryotic expression systems. The recombinant R2 purified by a two-step procedure exhibited a 3-fold higher activity when produced in eukaryotic cells. Precise quantification of the R2 concentration at each step of the purification indicated that the activity was not altered during the purification procedure. Moreover, we have observed that the level of R2 expression, in eukaryotic cells as well as in prokaryotic cells, did not influence R2 activity. Extensive characterization of the recombinant R2 purified from eukaryotic and prokaryotic expression systems has shown that both types of pure R2 preparations were similar in their 76 kDa dimer contents (more than 95%) and in their ability to bind the R1 subunit. However, we have found that the higher activity of R2 produced in eukaryotic cells is more probably related to a higher capability of binding the iron cofactor as well as a 3-fold greater ability to generate the tyrosyl free radical.

Magnetic studies of reduced iron clusters in the mouse R2 subunit of ribonucleotide reductase

1995 ◽  
Vol 59 (2-3) ◽  
pp. 372
Author(s):  
K.K. Andersson ◽  
M. Atta ◽  
N. Debaecker ◽  
J.-M. Latour ◽  
L. Thelander ◽  
...  
Keyword(s):  
Ribonucleotide Reductase ◽  
Magnetic Studies ◽  
Iron Clusters ◽  
R2 Subunit

Crystal structure of the R2 subunit of ribonucleotide reductase from Chlamydia trachomatis

2003 ◽  
Vol 96 (1) ◽  
pp. 235
Author(s):  
Pal Stenmark ◽  
Martin Högbom ◽  
Pär Nordlund ◽  
Grant McClarty
Keyword(s):  
Crystal Structure ◽  
Chlamydia Trachomatis ◽  
Ribonucleotide Reductase ◽  
R2 Subunit

scholarly journals Identification of Potent Inhibitors of ATP Synthase Subunit C (AtpE) from Mycobacterium Tuberculosis Using in Silico Approach

2020 ◽  
Author(s):  
Dr. Mustafa Alhaji Isa
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Binding Energy ◽  
Atp Synthase ◽  
Md Simulation ◽  
Binding Energies ◽  
Model Structure ◽  
Generalized Born ◽  
Subunit C ◽  
Docking Analysis ◽  
Pubchem Database

<p>ATP synthase subunit c (AtpE) is an enzyme that catalyzes the production of ATP from ADP in the presence of sodium or proton gradient from <i>Mycobacterium tuberculosis</i> (MTB). This enzyme considered an essential target for drug design and its shares the same pathway with the target of Isoniazid. Thus, this enzyme would serve as an alternative target of the Isoniazid. The 3D model structure of the AtpE was constructed based on the principle of the homology modeling using the Modeller9.16. The developed model was subjected to the energy minimization and refinement using molecular dynamic (MD) simulation. The minimized model structure was searched against Zinc and PubChem database to determine ligands that bind to the enzyme with minimum binding energy using RASPD and PyRx tool. A total of 4776 compounds capable of binding to AtpE with minimum binding energies were selected. These compounds further screened for physicochemical properties (Lipinski rule of five). All the compounds that possessed the desirable properties selected and used for molecular docking analysis. Five (5) compounds with minimum binding energies ranged between ─8.69, and ─8.44kcal/mol, less than the free binding energy of ATP were selected. These compound further screened for the absorption, distribution, metabolism, excretion, and toxicity (ADME and toxicity) properties. Of the five compounds, three (ZINC14732869, ZINC14742188, and ZINC12205447) fitted all the ADME and toxicity properties and subjected to MD simulation and Molecular Mechanics Generalized Born and Surface Area (MM-GBSA) analyses. The results indicated that the ligands formed relatively stable complexes and had free binding energies, less than the binding energy of the ATP. Therefore, these ligands considered as prospective inhibitors of MTB after successful experimental validation</p>

scholarly journals Investigation of the anti-TB potential of selected alkaloid constituents using molecular docking approach

2020 ◽  
Author(s):  
Mohammad Kawsar Sharif Siam ◽  
Mohammad Umer Sharif Shohan ◽  
Zaira Zafroon
Keyword(s):  
Free Energy ◽  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Protein Binding ◽  
Binding Free Energy ◽  
Chemical Constituents ◽  
Biological Evaluation ◽  
Natural Sources ◽  
Docking Score ◽  
Docking Approach

AbstractMycobacterium tuberculosis, the leading bacterial killer disease worldwide, causes Human tuberculosis (TB). Due to the growing problem of drug resistant Mycobacterium tuberculosis strains, new anti-TB drugs are urgently needed. Natural sources such as plant extracts have long played an important role in tuberculosis management and can be used as a template to design new drugs. A wide screening of natural sources is time consuming but the process can be significantly sped up using molecular docking. In this study, we used a molecular docking approach to investigate the interactions between selected natural constituents and three proteins MtPanK, MtDprE1 and MtKasA involved in the physiological functions of Mycobacterium tuberculosis which are necessary for the bacteria to survive and cause disease. The molecular docking score, a score that accounts for the binding affinity between a ligand and a target protein, for each protein was calculated against 150 chemical constituents of different classes to estimate the binding free energy. The docking scores represent the binding free energy. The best docking scores indicates the highest ligand protein binding which is indicated by the lowest energy value. Among the natural constituents, Shermilamine B showed a docking score of - 8.5kcal/mol, Brachystamide B showed a docking score of −8.6 kcal/mol with MtPanK, Monoamphilectine A showed a score of −9.8kcal/mol with MtDprE1.These three compounds showed docking scores which were superior to the control inhibitors and represent the opportunity of in vitro biological evaluation and anti-TB drug design. Consequently, all these compounds belonged to the alkaloid class. Specific interactions were studied to further understand the nature of intermolecular bonds between the most active ligands and the protein binding site residues which proved that among the constituents monoamphilectine A and Shermilamine B show more promise as Anti-TB drugs. Furthermore, the ADMET properties of these compounds or ligands showed that they have no corrosive or carcinogenic parameters.Graphical Abstract

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