Affinity capillary electrophoretic study of K+/Na+ selectivity of hexaarylbenzene-based polyaromatic receptor

Affinity capillary electrophoretic (ACE) study has proved the selectivity of hexaarylbenzene-based polyaromatic receptor (R) for K⁺ ion over Na⁺ ion. The apparent binding constants of the R complexes with K⁺ and Na⁺ ions were determined from the dependence of effective electrophoretic mobility of R on the concentration of the above alkali metal ions in the background electrolyte using a non-linear regression analysis. The apparent binding constants (K_b) of the K-R⁺ and Na–R⁺ complexes in methanolic medium were evaluated as log K_b = 3.20 ± 0.22 for the K–R⁺ complex, and log K_b??0.7 for the Na–R⁺ complex.     

Routing and wavelength assignment algorithms for multiclass WDM optical networks

In this paper dynamic routing and wavelength assignment strategies have been proposed for multiclass WDM optical networks. Multiclass optical networks provide multiple classes of services to the subscriber according to the requirement, which in turn increase operational profitability. Each class of service could be characterized by parameters like number of wavelengths, expected call holding time and average arrival rate of request. The proposed strategies have been analyzed and compared with existing strategies on the basis of blocking probabilities for multiclass traffic scenarios. Simulation results on different network topologies demonstrate that the performance of proposed strategies “Fixed shortest/alternate shortest path routing with wavelength reservation (FSASWR)” and “Fixed alternate shortest path routing with least priority wavelength assignment (FASPL)” are much better as compared to existing strategies. Proposed strategies minimize blocking probability of the multiclass network using limited number of wavelengths.     

Principal eigenvector field segmentation for reproducible diffusion tensor tractography of white matter structures

The study was aimed to test the feasibility of utilizing an algorithmically determinable stable fiber mass (SFM) map obtained by an unsupervised principal eigenvector field segmentation (PEVFS) for automatic delineation of 18 white matter (WM) tracts: (1) corpus callosum (CC), (2) tapetum (TP), (3) inferior longitudinal fasciculus (ILF), (4) uncinate fasciculus (UNC), (5) inferior fronto-occipital fasciculus (IFO), (6) optic pathways (OP), (7) superior longitudinal fasciculus (SLF), (8) arcuate fasciculus (AF), (9) fornix (FX), (10) cingulum (CG), (11) anterior thalamic radiation (ATR), (12) superior thalamic radiation (STR), (13) posterior thalamic radiation (PTR), (14) corticospinal/corticopontine tract (CST/CPT), (15) medial lemniscus (ML), (16) superior cerebellar peduncle (SCP), (17) middle cerebellar peduncle (MCP) and (18) inferior cerebellar peduncle (ICP). Diffusion tensor imaging (DTI)-derived fractional anisotropy (FA) and the principal eigenvector field have been used to create the SFM consisting of a collection of linear voxel structures which are grouped together by color-coding them into seven natural classes to provide PEVFS signature segments which greatly facilitate the selection of regions of interest (ROIs) for fiber tractography using just a single mouse click, as compared with a manual drawing of ROIs in the classical approach. All the 18 fiber bundles have been successfully reconstructed, in all the subjects, using the single ROIs provided by the SFM approach, with their reproducibility characterized by the fact that the ROI selection is user independent. The essentially automatic PEVFS method is robust, efficient and compares favorably with the classical ROI methods for diffusion tensor tractography (DTT).     

Serendipitous discovery of light-induced (<Emphasis Type="Italic">In Situ</Emphasis>) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor

Background

Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results.

Results

Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC₅₀ of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC₅₀ of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5.

Conclusion

We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds.

     

Affinity capillary electrophoresis and density functional theory employed for the characterization of hexaarylbenzene-based receptor complexation with alkali metal ions

In this study, affinity capillary electrophoresis (ACE) and quantum mechanical density functional theory (DFT) calculations were combined to investigate non-covalent binding interactions between the hexaarylbenzene-based receptor (R) and alkali metal ions, Rb(+) and Cs(+) , in methanol. The apparent binding (stability) constants (K(b) ) of the complexes of receptor R with alkali metal ions in the methanolic medium were determined by ACE from the dependence of effective electrophoretic mobility of the receptor R on the concentration of Rb(+) and Cs(+) ions in the BGE using a non-linear regression analysis. The receptor R formed relatively strong complexes both with rubidium (log K(b) =4.04±0.21) and cesium ions (log K(b) =3.72±0.22). The structural characteristics of the above alkali metal ion complexes with the receptor R were described by ab initio density functional theory calculations. These calculations have shown that the studied cations bind to the receptor R because they synergistically interact with the polar ethereal fence and with the central benzene ring via cation-π interaction.     

Minimum MD simulation length required to achieve reliable results in free energy perturbation calculations: Case study of relative binding free energies of fructose‐1,6‐bisphosphatase inhibitors

In an attempt to establish the criteria for the length of simulation to achieve the desired convergence of free energy calculations, two studies were carried out on chosen complexes of FBPase‐AMP mimics. Calculations were performed for varied length of simulations and for different starting configurations using both conventional‐ and QM/MM‐FEP methods. The results demonstrate that for small perturbations, 1248 ps simulation time could be regarded a reasonable yardstick to achieve convergence of the results. As the simulation time is extended, the errors associated with free energy calculations also gradually tapers off. Moreover, when starting the simulation from different initial configurations of the systems, the results are not changed significantly, when performed for 1248 ps. This study carried on FBPase‐AMP mimics corroborates well with our previous successful demonstration of requirement of simulation time for solvation studies, both by conventional and ab initio FEP. The establishment of aforementioned criteria of simulation length serves a useful benchmark in drug design efforts using FEP methodologies, to draw a meaningful and unequivocal conclusion. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011     

Experimental and theoretical study of the complexation of the thallium cation with a hexaarylbenzene-based receptor

Abstract  

From extraction experiments in the two-phase water/nitrobenzene system and γ-activity measurements, the stability constant of a hexaarylbenzene-based receptor. Tl⁺ complex species dissolved in nitrobenzene saturated with water was determined. By using the quantum-mechanical density functional level of theory calculations, the most probable structure of this complex was derived.     

On the local fractional wave equation in fractal strings

The key aim of the present study is to attain nondifferentiable solutions of extended wave equation by making use of a local fractional derivative describing fractal strings by applying local fractional homotopy perturbation Laplace transform scheme. The convergence and uniqueness of the obtained solution by using suggested scheme is also examined. To determine the computational efficiency of offered scheme, some numerical examples are discussed. The results extracted with the aid of this technique verify that the suggested algorithm is suitable to execute, and numerical computational work is very interesting.     

Amitriptylinium picrate: conformational disorder

In the structure of the title salt [systematic name: 3‐(10,11‐dihydro‐5H‐dibenzo[a,d][7]annulen‐5‐ylidene)‐N,N‐dimethylpropan‐1‐aminium 2,4,6‐trinitrophenolate] of a tricyclic antidepressant, C₂₀H₂₄N⁺·C₆H₂N₃O₇⁻, the dimethylaminopropyl subunit possesses a classical static conformational disorder. The central cycloheptadiene ring adopts a bent conformation that is intermediate between boat and chair forms, leading to a butterfly shape for the hetero‐tricyclic moiety. In a complementary fashion, donors from amitriptyline and acceptors from picrate form intermolecular C—H...O hydrogen bonds and N—H...O salt bridges. These hydrogen bonds cluster amitriptyline and picrate ions into a closed R₄⁴(36) hetero‐tetramer, whereas intermolecular C—H...π interactions between amitriptyline ions cluster them into homo‐dimers. Significant π–π stacking interactions are also observed between aromatic rings of amitriptyline and picrate, and these, combined with the C—H...π interactions, associate molecules into linear arrays along the [11] direction.