3-Substituted Anilines as Scaffolds for the Construction of Glutamine Synthetase and DXP-Reductoisomerase Inhibitors

Access to a series of truncated ATP analogs, as potential anti-tuberculosis agents, has been explored via alkylation and acylation of 3-aminophenol, whereas chloroacetylation, using chloroacetyl chloride, and subsequent Arbuzov phosphonation of a series of 3-substituted anilines have afforded a series of phosphonate derivatives as potential antimalarial agents.     

Virtual target screening: validation using kinase inhibitors

Computational methods involving virtual screening could potentially be employed to discover new biomolecular targets for an individual molecule of interest (MOI). However, existing scoring functions may not accurately differentiate proteins to which the MOI binds from a larger set of macromolecules in a protein structural database. An MOI will most likely have varying degrees of predicted binding affinities to many protein targets. However, correctly interpreting a docking score as a hit for the MOI docked to any individual protein can be problematic. In our method, which we term "Virtual Target Screening (VTS)", a set of small drug-like molecules are docked against each structure in the protein library to produce benchmark statistics. This calibration provides a reference for each protein so that hits can be identified for an MOI. VTS can then be used as tool for: drug repositioning (repurposing), specificity and toxicity testing, identifying potential metabolites, probing protein structures for allosteric sites, and testing focused libraries (collection of MOIs with similar chemotypes) for selectivity. To validate our VTS method, twenty kinase inhibitors were docked to a collection of calibrated protein structures. Here, we report our results where VTS predicted protein kinases as hits in preference to other proteins in our database. Concurrently, a graphical interface for VTS was developed.     

Corrigendum

Archive for Rational Mechanics and Analysis -     

Experimental results on J/ψ production by π±, K±, p and p incident on hydrogen at 39.5 GeV/c

J/ψ production at 40 GeV/c by π^±, K^±, p and $\text{p}$ incident on hydrogen has been studied and results compared with those obtained on tungsten in the same experiment. On hydrogen, J/ψ cross-section ratios relative to π^? have been measured to be (for $\text{x}{}_{\mathrm{<mtext>F</mtext>}}\text{> 0) σ(π}{}^{\mathrm{?}}\text{) : σ(π}{}^{\mathrm{+}}\text{) : σ(}\text{p}\text{) : σ(}\text{p}\text{) = 1 : (0.78 ± 0.09) : (0.83 ± 0.35) : (0.07 ± 0.04)}$. The suppression of the proton induced cross sections shows the importance of calence quark-antiquark fusiin J/ψ production at this energy (i.e. M_J²/_ψ/s=0.13).     

Electrophoretic exclusion for the selective transport of small molecules

A novel method capable of differentiating and concentrating small molecules in bulk solution termed “electrophoretic exclusion” is described and experimentally investigated. In this technique, the hydrodynamic flow of the system is countered by the electrophoretic velocity to prevent a species from entering into the channel. The separation can be controlled by changing the flow rate or applied electric field in order to exclude certain species selectively while allowing others to pass through the capillary. Proof of principle studies employed a flow injection regime of the method and examined the exclusion of Methyl Violet dye in the presence of a neutral species. Methyl Violet was concentrated almost 40 times the background concentration in 30 s using 6 kV. Additionally, a threshold voltage necessary for exclusion was determined. The establishment of a threshold voltage enabled the differentiation of two similar cationic species: Methyl Green and Neutral Red.     

Intersecting random translates of invariant Cantor sets

Summary Given two Cantor setsX andY in [0, 1), invariant under the mapxb x mod 1, the Hausdorff dimension of (X+t)Y is constant almost everywhere. WhenX,Y are defined by admissible digits in baseb, and more generally by sofic systems, we compute this dimension in terms of the largest Lyapunov exponent of a random product of matrices. The results are extended to higher dimensions and multiple intersections.Oblatum 17-VIII-1990Support was provided by an IBM fellowship.Partially supported by a grant from the Landau Centre for Mathematical Analysis     

Glauber dynamics on trees and hyperbolic graphs

We study continuous time Glauber dynamics for random configurations with local constraints (e.g. proper coloring, Ising and Potts models) on finite graphs with n vertices and of bounded degree. We show that the relaxation time (defined as the reciprocal of the spectral gap |₁–₂|) for the dynamics on trees and on planar hyperbolic graphs, is polynomial in n. For these hyperbolic graphs, this yields a general polynomial sampling algorithm for random configurations. We then show that for general graphs, if the relaxation time ₂ satisfies ₂=O(1), then the correlation coefficient, and the mutual information, between any local function (which depends only on the configuration in a fixed window) and the boundary conditions, decays exponentially in the distance between the window and the boundary. For the Ising model on a regular tree, this condition is sharp.Research supported by Microsoft graduate fellowship.Supported by a visiting position at INRIA and a PostDoc at Microsoft research.Research supported by NSF Grants DMS-0104073, CCR-0121555 and a Miller Professorship at UC Berkeley.Acknowledgement We are grateful to David Aldous, David Levin, Laurent Saloff-Coste and Peter Winkler for useful discussions. We thank Dror Weitz for helpful comments on [19].     

A variational principle for domino tilings

We formulate and prove a variational principle (in the sense of thermodynamics) for random domino tilings, or equivalently for the dimer model on a square grid. This principle states that a typical tiling of an arbitrary finite region can be described by a function that maximizes an entropy integral. We associate an entropy to every sort of local behavior domino tilings can exhibit, and prove that almost all tilings lie within (for an appropriate metric) of the unique entropy-maximizing solution. This gives a solution to the dimer problem with fully general boundary conditions, thereby resolving an issue first raised by Kasteleyn. Our methods also apply to dimer models on other grids and their associated tiling models, such as tilings of the plane by three orientations of unit lozenges.

     

Hausdorff dimensions of sofic affine-invariant sets

We determine the Hausdorff and Minkowski dimensions of compact subsets of the 2-torus which are invariant under a linear endomorphism with integer eigenvalues and correspond to shifts of finite type or sofic shifts via some Markov partition. This extends a result of McMullen (1984) and Bedford (1984), who considered full-shifts. This work was completed while the first author was at the Institut Fourier, Grenoble, France, and at MSRI, Berkeley, CA. The research at MSRI was supported in part by NSF grant #DMS 9022140. This work was completed while the second author was at Yale University. Received July 8, 1994