Efficient generation,storage, and manipulation of fully flexible pharmacophore multiplets and their use in 3-D similarity searching

Pharmacophore triplets and quartets have been used by many groups in recent years, primarily as a tool for molecular diversity analysis. In most cases, slow processing speeds and the very large size of the bitsets generated have forced researchers to compromise in terms of how such multiplets were stored, manipulated, and compared, e.g., by using simple unions to represent multiplets for sets of molecules. Here we report using bitmaps in place of bitsets to reduce storage demands and to improve processing speed. Here, a bitset is taken to mean a fully enumerated string of zeros and ones, from which a compressed bitmap is obtained by replacing uniform blocks ("runs") of digits in the bitset with a pair of values identifying the content and length of the block (run-length encoding compression). High-resolution multiplets involving four features are enabled by using 64 bit executables to create and manipulate bitmaps, which "connect" to the 32 bit executables used for database access and feature identification via an extensible mark-up language (XML) data stream. The encoding system used supports simple pairs, triplets, and quartets; multiplets in which a privileged substructure is used as an anchor point; and augmented multiplets in which an additional vertex is added to represent a contingent feature such as a hydrogen bond extension point linked to a complementary feature (e.g., a donor or an acceptor atom) in a base pair or triplet. It can readily be extended to larger, more complex multiplets as well. Database searching is one particular potential application for this technology. Consensus bitmaps built up from active ligands identified in preliminary screening can be used to generate hypothesis bitmaps, a process which includes allowance for differential weighting to allow greater emphasis to be placed on bits arising from multiplets expected to be particularly discriminating. Such hypothesis bitmaps are shown to be useful queries for database searching, successfully retrieving active compounds across a range of structural classes from a corporate database. The current implementation allows multiconformer bitmaps to be obtained from pregenerated conformations or by random perturbation on-the-fly. The latter application involves random sampling of the full range of conformations not precluded by steric clashes, which limits the usefulness of classical fingerprint similarity measures. A new measure of similarity, The Stochastic Cosine, is introduced here to address this need. This new similarity measure uses the average number of bits common to independently drawn conformer sets to normalize the cosine coefficient. Its use frees the user from having to ensure strict comparability of starting conformations and having to use fixed torsional increments, thereby allowing fully flexible characterization of pharmacophoric patterns.     

Relations between 77Se NMR chemical shifts of (phenylseleno)-benzenes and their molecular structures derived from nine X-ray crystal structures

An extensive library of 77Se chemical shifts have been generated from the NMR measurements on substituted (phenylseleno)benzenes, including 33 new compounds. The variation in chemical shifts cover 265 ppm ranging from 446 to 181 ppm. Crystal structures have been determined for nine selected representatives of the substituted (phenylseleno)-benzenes. The analysis of the crystal structures supported that through-space interactions between selenium and the ortho-substituent observed in the crystal structures also are likely to be present in solution. The variation in the 77Se NMR chemical shifts can be rationalised from the intramolecular interactions with the substituent in the ortho-position. Furthermore it appears that these ortho-effects are roughly additive, and that it is the actual interactions and not the resulting conformational constraints that are responsible for the variations in the 77Se NMR chemical shifts.     

Water-compatible molecularly imprinted polymers obtained via high-throughput synthesis and experimental design

A technique allowing high-throughput synthesis and evaluation of molecularly imprinted polymer sorbents at a reduced scale (mini-MIPs) was developed and used for the optimization of MIPs for use in pure aqueous environments. The technique incorporated a 4-port liquid-handling robot for the rapid dispensing of monomers, templates, solvents and initiator into the reaction vessels of a 96-well plate. A library of 80 polymers, each ca. 50 mg, could thus be prepared in 24 h. The MIP rebinding capacity and selectivity could be rapidly assessed in the batch mode by quantifying nonbound fractions in parallel using a UV monochromator plate reader. This allowed a complete evaluation of the binding characteristics of an 80 polymer library in approximately 1 week. With the objective of optimizing a polymer imprinted with the local anaesthetic Bupivacaine for use in pure aqueous systems, a polymer library was prepared by varying the original poly(MAA-co-EDMA) MIP composition. The variable factors were the added amount of the hydrophilic comonomer, 2-hydroxyethyl methacrylate (HEMA), the cross-linking ratio, and the porogen. This optimization resulted in polymers showing high imprinting factors (IF = K(MIP)/K(NIP)) in water as a result, mainly, of reduced binding to the nonimprinted polymer. Normal scale batches of these materials showed strong retention of the template and low nonspecific binding when assessed as chromatographic stationary phases using pure phosphate buffer, pH 7.4, as mobile phase, by equilibrium batch rebinding experiments and as sorbents for extractions of the analyte from blood plasma samples.     

Hopf algebroids and H-separable extensions

Since an H-separable extension is of depth two, we associate to it dual bialgebroids and over the centralizer as in Kadison-Szlachányi. We show that has an antipode and is a Hopf algebroid. is also Hopf algebroid under the condition that the centralizer is an Azumaya algebra over the center of . For depth two extension , we show that .

     

On the vanishing of negative K-groups

We show that for a d-dimensional scheme X essentially of finite type over an infinite perfect field k of characteristic p > 0, the negative K-groups K _q (X) vanish for q < ?d provided that strong resolution of singularities holds over the field k.     

Programmable interferometry

The advent of automatic data-processing for interferometry greatly reduced the complexity of interferometric testing, thereby significantly increasing its usage both within and outside the optics community. A great many of these new applications require special data-processing and output data not normally used for testing lenses. To address these new measurement problems, many data-analysis programs were written, ranging from advanced analysis of wavefronts (i.e., Zernike polynominals, point-spread function, modulation-transfer function) to analysis of mechanical surfaces, such as Winchester-disk read/write heads. Some of these programs were very specific to a particular application, and some tried to be general and as such became cumbersome. Even with much of this software available for sale to the general public, most applications other than simple surface and lens measurements usually cannot be solved directly by using the available programs. In an attempt to solve this problem, we have developed software for interferometry that allows users to easily develop their own measurement routines. The solution was to take a version of the BASIC programming language and add the commands necessary to do interferometry. This software is resident in a processor that can easily be adapted to a large number of interferometry applications. By using this processor and its associated software with an appropriate interferometer, it is possible for the user to tailor the measurement to a particular application. This can be very useful in an optical-production shop, where each different testing application can have its own program. If the program is written properly, the operator will not have to set up any default conditions or format the output; the operation of the program can be reduced to the pushing of a single button, and the output will be formatted properly for that particular test. Examples of this system in actual optical shop-testing situations will be discussed.     

Adsorption of polyallylamine to lignocellulosic fibres: effect of adsorption conditions on localisation of adsorbed polyelectrolyte and mechanical properties of resulting paper sheets

Cationic polyallylamine (PAH), was adsorbed onto lignocellulosic fibres, and a fluorescent label on the polyelectrolyte enabled its location to be shown by confocal fluorescence microscopy. The adsorption time and ionic strength were varied to study their effect on the localisation of the adsorbed PAH. The microscopy showed that a long adsorption time, 24 h, and a high ionic strength, 10⁻¹ M NaCl + 5 × 10⁻³ M NaHCO₃ or higher, resulted in the adsorption of polyallylamine throughout the fibre walls. Shorter adsorption times and/or lower ionic strength resulted in adsorption only to the fibre exterior. By preparing sheets from fibres with polyelectrolyte adsorbed either to the exterior parts or into the fibre cell wall and testing their mechanical behaviour, a link was established between the localisation of adsorbed polyelectrolyte and the mechanical properties. Adsorption to the fibre exterior led to an increase in tensile strength and strain at break. The creep deformation at 90%RH was also slightly reduced by the adsorption of low molecular weight PAH (15 kDa). When polyallylamine was adsorbed throughout the wall of the lignocellulosic fibres, the mechanical properties were not however improved and the creep deformation at 90%RH actually increased somewhat.     

A Uniform Exponential Spectrum for Linear Flows on Vector Bundles

For linear flows on vector bundles we define a uniform exponential spectrum. For a compact invariant set for the projected flow we obtain this spectrum by taking all accumulation points for the time tending to infinity of the union over the finite time exponential growth rates for all initial values in this set. Using direct arguments we show that for a connected compact invariant set this spectrum is a closed interval whose boundary points are Lyapunov exponents. For a compact invariant set on which the flow is chain transitive we show that this spectrum coincides with the Morse spectrum. In particular, this approach admits a straightforward analytic proof for the regularity and continuity properties of the Morse spectrum without using cohomology or ergodicity results.     

2,2′,6,6′-Tetrachloro-4,4′-propane-2,2-diyldiphenol, 2,2′,6-tribromo-4,4′-propane-2,2-diyldiphenol and 2,2′,6,6′-tetrabromo-4,4′-propane-2,2-diyldiphenol

Three flame retardants with very similar molecular structures showing three different packing patterns have been studied. The crystal structure of 2,2′,6,6′-tetrachloro-4,4′-propane-2,2-diyldiphenol, C₁₅H₁₂Cl₄O₂, can be described as a packing of sheets. The packing shows a very short intermolecular Cl⋯Cl contact distance of 3.094 (2) Å between pairs of mol­ecules inside each sheet. The crystal structure of 2,2′,6-tribromo-4,4′-propane-2,2-diyldiphenol, C₁₅H₁₃Br₃O₂, can be described as a packing of doubly stranded helical square tubes. These square helices are interconnected through Br⋯Br contacts between different helices. Finally, a previously known structure, 2,2′,6,6′-tetrabromo-4,4′-propane-2,2-diyldiphenol [Simonov, Cheban, Rotaru & Bels'skii (1986). Kristallografiya, 31 , 397–399], C₁₅H₁₂Br₄O₂, which is the most commonly used flame retardant and which has twofold rotational symmetry, has been refined in the correct absolute configuration. The structure shows large differences from the chloro analogue with regard to packing, van der Waals distances and hydrogen-bond distances.