scholarly journals Structure-guided design of a novel class of benzyl-sulfonate inhibitors for influenza virus neuraminidase

2006 ◽  
Vol 399 (2) ◽  
pp. 215-223 ◽  
Author(s):  
Dimitris Platis ◽  
Brian J. Smith ◽  
Trevor Huyton ◽  
Nikolaos E. Labrou
Keyword(s):  
Structural Information ◽  
Sulfate Ions ◽  
X Ray ◽  
Affinity Labelling ◽  
Molecular Modelling Studies ◽  
Cibacron Blue 3Ga ◽  
Modelling Studies ◽  
Infected Cells ◽  
Influenza Virus Neuraminidase ◽  
Triazine Dye

Influenza NA (neuraminidase) is an antiviral target of high pharmaceutical interest because of its essential role in cleaving sialic acid residues from cell surface glycoproteins and facilitating release of virions from infected cells. The present paper describes the use of structural information in the progressive design from a lead binding ion (a sulfate) to a potent submicromolor inhibitor (Ki 0.13 μM). Structural information derived from the X-ray structure of an NA complexed with several sulfate ions, in combination with results derived from affinity labelling and molecular modelling studies, was used to guide design of potent sulfonic acid-based inhibitors. These inhibitors are structural fragments of the polysulfonate triazine dye Cibacron Blue 3GA and represent novel lead scaffolds for designing non-carbohydrate inhibitors for influenza neuraminidases.

The Influence of the Axial Ligands of a Series of Platinum(IV) Anti-Cancer Complexes on Their Reduction to Platinum(II) and Reaction With DNA

1995 ◽  
Vol 48 (4) ◽  
pp. 793 ◽  
Author(s):  
LT Ellis ◽  
HM Er ◽  
TW Hambley
Keyword(s):  
Crystal Structure ◽  
Monoclinic Space Group ◽  
X Ray Diffraction ◽  
X Ray ◽  
Reduction Potentials ◽  
Axial Ligands ◽  
Carboxylate Anions ◽  
Anti Cancer ◽  
Molecular Modelling Studies ◽  
Modelling Studies

The electrochemical reduction and DNA binding have been studied for a series of platinum(IV) complexes with Cl-, OH-, and carboxylate anions as the axial ligands ; [Pt(en)Cl4], [Pt(en)Cl2(OH)2], and [Pt(en)Cl2(OC(O)R)2], R = CH3, CH2CH3, CH2CH2CH3. Cathodic reduction potentials vary by more than 650 mV with the tetrachloro complex reduced most readily and the dihydroxo least readily. The binding of the complexes correlates with the reduction potentials with the more readily reduced complexes binding more readily to DNA. The influence of the reducing agent glutathione on platinum binding to DNA was found to depend on whether it was added before or after Pt/DNA incubation. The results are consistent with octahedral platinum(IV) binding monofunctionally to DNA, and molecular modelling studies have been used to confirm that this is sterically feasible. The crystal structure of [Pt(en)Cl2(OC(O)CH3)2] has been determined by X-ray diffraction methods and refined to R = 0.028 (977 F). The crystals are monoclinic, space group C2/c, a 15.569(6), b 8.104(1), c 13.188(1) Ǻ, β 136.38(2)°.

The interaction of Schistosoma japonicum glutathione transferase with Cibacron blue 3GA and its fragments

2020 ◽  
Vol 16 ◽  
Author(s):  
Michalis Platis ◽  
Dimitrios Vlachakis ◽  
Ahmed Ibrahim Foudah ◽  
Magdy Mohamed Muharram ◽  
Mohamed Hamed Alqarni ◽  
...  
Keyword(s):  
Schistosoma Japonicum ◽  
Molecular Modelling ◽  
Glutathione Transferase ◽  
Cibacron Blue ◽  
Affinity Labelling ◽  
Inhibitory Strength ◽  
Cibacron Blue 3Ga ◽  
Modelling Studies ◽  
Kinetic Inhibition ◽  
Dynamics Simulations

Background: The 26kDa glutathione transferase (GST, EC 2.5.1.18) from Schistosoma japonicum (SjGST) is recognized as the major detoxification enzyme of S. japonicum, a pathogenic helminth causing schistosomiasis. Objective: In the present study, the interaction of the chlorotriazine dye Cibacron blue 3GA (CB3GA) and its structural analogues with SjGST was investigated. The work aimed to shine light on the non-substrate ligand-binding properties of the enzyme. Methods: Kinetic inhibition analysis, affinity labelling experiments and molecular modelling studies were employed. Results: The results showed that CB3GA is a potent inhibitor (IC50 0.057 ± 0.003μM) towards SjGST. The enzyme was specifically and irreversibly inactivated by the dichlorotriazine-analogue of CB3GA (IC50 0.190 ± 0.024 μM), following a biphasic pseudo-first-order saturation kinetics with approximately 1 mol of inhibitor per mol of dimeric enzyme being incorporated. All other monochlorotriazine analogues behave as reversible inhibitors with lower inhibition potency (IC50 5.2-82.3 μM). Kinetic inhibition studies together with molecular modelling and molecular dynamics simulations established that the CB3GA binding site overlaps both the G- and H-sites. Both hydrophobic/polar interactions as well as steric effects have decisive roles in determining the inhibitory strength of CB3GA and its analogues. Conclusion: The results of the present study might be useful in future drug design and development efforts towards SjGST.

New monocyclic and acyclic hNK-2 antagonists retaining the β-turn feature. X-ray and molecular modelling studies

2006 ◽  
Vol 62 (5) ◽  
pp. 889-896 ◽  
Author(s):  
Maria Altamura ◽  
Paolo Dapporto ◽  
Valentina Fedi ◽  
Alessandro Giolitti ◽  
Annalisa Guerri ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Structure Determination ◽  
Experimental Validation ◽  
Receptor Antagonists ◽  
X Ray ◽  
Promising Target ◽  
Molecular Modelling Studies ◽  
Modelling Studies ◽  
Turn Structure

The human tachykinin NK-2 (hNK-2) receptor is considered a promising target for relevant pathologies at the respiratory, gastrointestinal and genitourinary level. With the aim of reducing the complexity of existing peptide antagonists, two series of hNK-2 receptor antagonists were designed, with the support of modelling, and synthesized. The X-ray structure determination of two compounds, each belonging to one of the two series, allowed the experimental validation of the initial rationale. In addition, it has been found that the two series share a β-turn structure, a key feature for binding the hNK-2 receptor.

X-ray and molecular modelling studies of 4-[N-alkylamino]azobenzene dyes

2009 ◽  
Vol 82 (3) ◽  
pp. 299-306 ◽  
Author(s):  
Liang He ◽  
Ahmed El-Shafei ◽  
Harold S. Freeman ◽  
Paul Boyle
Keyword(s):  
Molecular Modelling ◽  
X Ray ◽  
Molecular Modelling Studies ◽  
Modelling Studies

scholarly journals Isolation, characterization, molecular cloning and molecular modelling of two lectins of different specificities from bluebell (Scilla campanulata) bulbs

1999 ◽  
Vol 340 (1) ◽  
pp. 299-308 ◽  
Author(s):  
Lisa M. WRIGHT ◽  
Els J. M. VAN DAMME ◽  
Annick BARRE ◽  
Anthony K. ALLEN ◽  
Fred VAN LEUVEN ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Close Relationships ◽  
Crystallographic Analysis ◽  
Amino Acid Residues ◽  
Refined Model ◽  
X Ray ◽  
Mannose Binding ◽  
Molecular Modelling Studies ◽  
Modelling Studies ◽  
Binding Lectin

Two lectins have been isolated from bluebell (Scilla campanulata) bulbs. From their isolation by affinity chromatography, they are characterized as a mannose-binding lectin (SCAman) and a fetuin-binding lectin (SCAfet). SCAman preferentially binds oligosaccharides with α(1,3)- and α(1,6)-linked mannopyranosides. It is a tetramer of four identical protomers of approx. 13 kDa containing 119 amino acid residues; it is not glycosylated. The fetuin-binding lectin (SCAfet), which is not inhibited by any simple sugars, is also unglycosylated. It is a tetramer of four identical subunits of approx. 28 kDa containing 244 residues. Each 28 kDa subunit is composed of two 14 kDa domains. Both lectins have been cloned from a cDNA library and sequenced. X-ray crystallographic analysis and molecular modelling studies have demonstrated close relationships in sequence and structure between these lectins and other monocot mannose-binding lectins. A refined model of the molecular evolution of the monocot mannose-binding lectins is proposed.

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