Complexation of nucleotide bases by molecular tweezers with active site carboxylic acids: effects of microenvironment

1991 ◽  
Vol 113 (1) ◽  
pp. 196-201 ◽  
Author(s):  
Steven C. Zimmerman ◽  
Weiming Wu ◽  
Zijian Zeng
Keyword(s):  
Carboxylic Acids ◽  
Active Site ◽  
Molecular Tweezers ◽  
Nucleotide Bases

Synthesis and structure of molecular tweezers containing active site functionality

1991 ◽  
Vol 113 (1) ◽  
pp. 183-196 ◽  
Author(s):  
Steven C. Zimmerman ◽  
Zijian Zeng ◽  
Weiming Wu ◽  
David E. Reichert
Keyword(s):  
Active Site ◽  
Molecular Tweezers

scholarly journals Design of Novel Bioisosteres of β-Diketo Acid Inhibitors of HIV-1 Integrase

2005 ◽  
Vol 16 (1) ◽  
pp. 41-61 ◽  
Author(s):  
Mario Sechi ◽  
Luciano Sannia ◽  
Fabrizio Carta ◽  
Michele Palomba ◽  
Roberto Dallocchio ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Drug Design ◽  
Carboxylic Acids ◽  
Active Site ◽  
Docking Studies ◽  
Design Strategies ◽  
Structure Based Drug Design ◽  
Computational Docking ◽  
Lead Compounds ◽  
Hiv 1

HIV-1 integrase (IN) is an attractive and validated target for the development of novel therapeutics against AIDS. Significant efforts have been devoted to the identification of IN inhibitors using various methods. In this context, through virtual screening of the NCI database and structure-based drug design strategies, we identified several pharmacophoric fragments and incorporated them on various aromatic or heteroaromatic rings. In addition, we designed and synthesized a series of 5-aryl(heteroaryl)-isoxazole-3-carboxylic acids as biological isosteric analogues of β-diketo acid containing inhibitors of HIV-1 IN and their derivatives. Further computational docking studies were performed to investigate the mode of interactions of the most active ligands with the IN active site. Results suggested that some of the tested compounds could be considered as lead compounds and suitable for further optimization.

ChemInform Abstract: Synthesis and Structure of Molecular Tweezers Containing Active Site Functionality.

ChemInform ◽  
2010 ◽  
Vol 22 (15) ◽  
pp. no-no
Author(s):  
S. C. ZIMMERMAN ◽  
Z. ZENG ◽  
W. WU ◽  
D. E. REICHERT
Keyword(s):  
Active Site ◽  
Molecular Tweezers

A Combined Crystallographic and Theoretical Study Explains the Capability of Carboxylic Acids to Adopt Multiple Binding Modes in the Active Site of Carbonic Anhydrases

2015 ◽  
Vol 22 (1) ◽  
pp. 97-100 ◽  
Author(s):  
Emma Langella ◽  
Katia D'Ambrosio ◽  
Melissa D'Ascenzio ◽  
Simone Carradori ◽  
Simona M. Monti ◽  
...  
Keyword(s):  
Carboxylic Acids ◽  
Active Site ◽  
Theoretical Study ◽  
Carbonic Anhydrases ◽  
Binding Modes ◽  
Multiple Binding

scholarly journals Studies towards the Design and Synthesis of Novel 1,5-Diaryl-1H-imidazole-4-carboxylic Acids and 1,5-Diaryl-1H-imidazole-4-carbohydrazides as Host LEDGF/p75 and HIV-1 Integrase Interaction Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6203
Author(s):  
Thompho J. Rashamuse ◽  
Muhammad Q. Fish ◽  
E. Mabel Coyanis ◽  
Moira L. Bode
Keyword(s):  
Western Blot ◽  
Carboxylic Acids ◽  
Active Site ◽  
Binding Pocket ◽  
Strand Transfer ◽  
Inhibition Assay ◽  
Design And Synthesis ◽  
A Cell ◽  
Inhibitory Threshold ◽  
Hiv 1

Two targeted sets of novel 1,5-diaryl-1H-imidazole-4-carboxylic acids 10 and carbohydrazides 11 were designed and synthesized from their corresponding ester intermediates 17, which were prepared via cycloaddition of ethyl isocyanoacetate 16 and diarylimidoyl chlorides 15. Evaluation of these new target scaffolds in the AlphaScreenTM HIV-1 IN-LEDGF/p75 inhibition assay identified seventeen compounds exceeding the pre-defined 50% inhibitory threshold at 100 µM concentration. Further evaluation of these compounds in the HIV-1 IN strand transfer assay at 100 μM showed that none of the compounds (with the exception of 10a, 10l, and 11k, with marginal inhibitory percentages) were actively bound to the active site, indicating that they are selectively binding to the LEDGF/p75-binding pocket. In a cell-based HIV-1 antiviral assay, compounds 11a, 11b, 11g, and 11h exhibited moderate antiviral percentage inhibition of 33–45% with cytotoxicity (CC50) values of >200 µM, 158.4 µM, >200 µM, and 50.4 µM, respectively. The antiviral inhibitory activity displayed by 11h was attributed to its toxicity. Upon further validation of their ability to induce multimerization in a Western blot gel assay, compounds 11a, 11b, and 11h appeared to increase higher-order forms of IN.

Locating Al in the DABCO catalyst before and after Al extraction

1990 ◽  
Vol 48 (4) ◽  
pp. 265-267
Author(s):  
Kathleen B. Reuter
Keyword(s):  
Active Site ◽  
Inverse Relationship ◽  
Transverse Direction ◽  
Reaction Rate ◽  
Acid Phosphate ◽  
Fracture Surfaces ◽  
Al Content ◽  
Before And After ◽  
Relationship Of

The reaction rate and efficiency of piperazine to 1,4-diazabicyclo-octane (DABCO) depends on the Si/Al ratio of the MFI topology catalysts. The Al was shown to be the active site, however, in the Si/Al range of 30-200 the reaction rate increases as the Si/Al ratio increases. The objective of this work was to determine the location and concentration of Al to explain this inverse relationship of Al content with reaction rate.Two silicalite catalysts in the form of 1/16 inch SiO2/Al2O3 bonded extrudates were examined: catalyst A with a Si/Al of 83; and catalyst B, the acid/phosphate Al extracted form of catalyst A, with a Si/Al of 175. Five extrudates from each catalyst were fractured in the transverse direction and particles were obtained from the fracture surfaces near the center of the extrudate diameter. Particles were also obtained from the outside surfaces of five extrudates.

Structures of c-di-GMP/cGAMP degrading phosphodiesterase VcEAL: identification of a novel conformational switch and its implication

2019 ◽  
Vol 476 (21) ◽  
pp. 3333-3353 ◽  
Author(s):  
Malti Yadav ◽  
Kamalendu Pal ◽  
Udayaditya Sen
Keyword(s):  
Active Site ◽  
Metal Binding ◽  
Metal Ion ◽  
Triosephosphate Isomerase ◽  
Catalytic Mechanism ◽  
Degradation Mechanism ◽  
Structural Basis ◽  
Conserved Residues ◽  
Phosphodiester Bond ◽  
Cyclic Dinucleotides

Cyclic dinucleotides (CDNs) have emerged as the central molecules that aid bacteria to adapt and thrive in changing environmental conditions. Therefore, tight regulation of intracellular CDN concentration by counteracting the action of dinucleotide cyclases and phosphodiesterases (PDEs) is critical. Here, we demonstrate that a putative stand-alone EAL domain PDE from Vibrio cholerae (VcEAL) is capable to degrade both the second messenger c-di-GMP and hybrid 3′3′-cyclic GMP–AMP (cGAMP). To unveil their degradation mechanism, we have determined high-resolution crystal structures of VcEAL with Ca2+, c-di-GMP-Ca2+, 5′-pGpG-Ca2+ and cGAMP-Ca2+, the latter provides the first structural basis of cGAMP hydrolysis. Structural studies reveal a typical triosephosphate isomerase barrel-fold with substrate c-di-GMP/cGAMP bound in an extended conformation. Highly conserved residues specifically bind the guanine base of c-di-GMP/cGAMP in the G2 site while the semi-conserved nature of residues at the G1 site could act as a specificity determinant. Two metal ions, co-ordinated with six stubbornly conserved residues and two non-bridging scissile phosphate oxygens of c-di-GMP/cGAMP, activate a water molecule for an in-line attack on the phosphodiester bond, supporting two-metal ion-based catalytic mechanism. PDE activity and biofilm assays of several prudently designed mutants collectively demonstrate that VcEAL active site is charge and size optimized. Intriguingly, in VcEAL-5′-pGpG-Ca2+ structure, β5–α5 loop adopts a novel conformation that along with conserved E131 creates a new metal-binding site. This novel conformation along with several subtle changes in the active site designate VcEAL-5′-pGpG-Ca2+ structure quite different from other 5′-pGpG bound structures reported earlier.

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