CiteULike: Tag chemical

Encoded self-assembling chemical libraries

Samu Melkko — 2005-11-24T10:27:10-00:00

Nat Biotech, Vol. 22, No. 5. (May 2004), pp. 568-574.

Protein Kinase Inhibitors: Insights into Drug Design from Structure

Martin Noble — 2005-09-19T09:54:40-00:00

Science, Vol. 303, No. 5665. (19 March 2004), pp. 1800-1805.

Protein kinases are targets for treatment of a number of diseases. This review focuses on kinase inhibitors that are in the clinic or in clinical trials and for which structural information is available. Structures have informed drug design and have illuminated the mechanism of inhibition. We review progress with the receptor tyrosine kinases (growth factor receptors EGFR, VEGFR, and FGFR) and nonreceptor tyrosine kinases (Bcr-Abl), where advances have been made with cancer therapeutic agents such as Herceptin and Gleevec. Among the serine-threonine kinases, p38, Rho-kinase, cyclin-dependent kinases, and Chk1 have been targeted with productive results for inflammation and cancer. Structures have provided insights into targeting the inactive or active form of the kinase, for targeting the global constellation of residues at the ATP site or less conserved additional pockets or single residues, and into targeting noncatalytic domains.

A small molecule–kinase interaction map for clinical kinase inhibitors

Miles Fabian — 2005-03-04T21:58:37-00:00

Nature Biotechnology, Vol. 23, No. 3. (13 February 2005), pp. 329-336.

Toward a pharmacophore for kinase frequent hitters.

AM Aronov — 2006-02-07T18:05:07-00:00

J Med Chem, Vol. 47, No. 23. (4 November 2004), pp. 5616-5619.

Small molecule protein kinase inhibitors are widely employed as biological reagents and as leads in the design of drugs for a variety of diseases. One of the hardest challenges in kinase inhibitor design is achieving target selectivity. By utilizing X-ray structural information for four promiscuous inhibitors, we propose a five-point pharmacophore for kinase frequent hitters, demonstrate its ability to discriminate between frequent hitters and selective ligands, and suggest a strategy for selective inhibitor design.

Features of selective kinase inhibitors.

ZA Knight — 2005-09-14T16:42:40-00:00

Chem Biol, Vol. 12, No. 6. (June 2005), pp. 621-637.

Small-molecule inhibitors of protein and lipid kinases have emerged as indispensable tools for studying signal transduction. Despite the widespread use of these reagents, there is little consensus about the biochemical criteria that define their potency and selectivity in cells. We discuss some of the features that determine the cellular activity of kinase inhibitors and propose a framework for interpreting inhibitor selectivity.

A New Data Analysis Method to Determine Binding Constants of Small Molecules to Proteins Using Equilibrium Analytical Ultracentrifugation with Absorption Optics

Michelle Arkin — 2005-03-03T09:10:56-00:00

Analytical Biochemistry, Vol. 299, No. 1. (01 December 2001), pp. 98-107.

In principle, equilibrium analytical ultracentrifugation (AU) can be used to quantify the binding stoichiometry and affinity between small-molecule ligands and proteins in aqueous solution. We show here that heteromeric binding constants can be determined using a data-fitting procedure which utilizes a postfitting computation of the total amount of each component in the centrifuge cell. The method avoids overconstraining the fitting of the radial concentration profiles, but still permits unique binding constants to be determined using measurements at a single wavelength. The computational program is demonstrated by applying it to data obtained with mixtures of a 500-Da molecule and interleukin-2, a 16-kDa protein. The 1:1 binding stoichiometry and heteromeric dissociation constants (Kab) determined from centrifuge data at two different wavelengths are within the 4-9 [mu]M range independently determined from a functional assay. Values for Kab have been obtained for ligands with affinities as weak as 500 [mu]M. This AU method is applicable to compounds with significant UV absorbance (~0.2) at concentrations within ~5- to 10-fold of their Kab. The method, which has been incorporated into a user procedure for IgorPro (Wavemetrics, Oswego, OR), is included as supplementary material.

Chemical Rescue of a Mutant Enzyme in Living Cells

Yingfeng Qiao — 2006-03-03T10:25:22-00:00

Science, Vol. 311, No. 5765. (3 March 2006), pp. 1293-1297.

The restoration of catalytic activity to mutant enzymes by small molecules is well established for in vitro systems. Here, we show that the protein tyrosine kinase Src arginine-388[->]alanine (R388A) mutant can be rescued in live cells with the use of the small molecule imidazole. Cellular rescue of a viral Src homolog was rapid and reversible and conferred predicted oncogenic properties. Using chemical rescue in combination with mass spectrometry, we confirmed six known Src kinase substrates and identified several new protein targets. Chemical rescue data suggest that cellular Src is active under basal conditions. Rescue of R388A cellular Src provided insights into the mitogen-activated protein kinase pathway. This chemical rescue approach will likely have many applications in cell signaling.

Lessons from natural molecules

Jon Clardy — 2004-12-16T13:06:15-00:00

Nature, Vol. 432, No. 7019. (16 December 2004), pp. 829-837.

Medicinal chemistry of target family-directed masterkeys.

G Müller — 2005-11-25T09:12:00-00:00

Drug Discov Today, Vol. 8, No. 15. (1 August 2003), pp. 681-691.

The majority of pharmaceutically relevant drug targets cluster into densely populated target families, thus offering a novel approach that complements the currently favoured screening paradigm in medicinal chemistry. This approach uses a privileged structure concept whereby molecular masterkeys are developed that account for a target family wide structural or functional commonality. Numerous lead compounds, based on multipurpose privileged structures, can be generated that address a variety of targets from a gene family of interest, irrespective of therapeutic area. Several different interpretations of the privileged structure concept will be highlighted, with a strong emphasis on the most stringent application: the optimization of a molecular masterkey for a distinct target family of interest.

Chemical communicationChirality in elephant pheromones

David Greenwood — 2005-12-21T22:41:16-00:00

Nature, Vol. 438, No. 7071. (21 December 2005), pp. 1097-1098.

The inheritance of chemical phenotype in Cannabis sativa L.

EP de Meijer — 2008-05-26T17:24:16-00:00

Genetics, Vol. 163, No. 1. (January 2003), pp. 335-346.

Four crosses were made between inbred Cannabis sativa plants with pure cannabidiol (CBD) and pure Delta-9-tetrahydrocannabinol (THC) chemotypes. All the plants belonging to the F(1)'s were analyzed by gas chromatography for cannabinoid composition and constantly found to have a mixed CBD-THC chemotype. Ten individual F(1) plants were self-fertilized, and 10 inbred F(2) offspring were collected and analyzed. In all cases, a segregation of the three chemotypes (pure CBD, mixed CBD-THC, and pure THC) fitting a 1:2:1 proportion was observed. The CBD/THC ratio was found to be significantly progeny specific and transmitted from each F(1) to the F(2)'s derived from it. A model involving one locus, B, with two alleles, B(D) and B(T), is proposed, with the two alleles being codominant. The mixed chemotypes are interpreted as due to the genotype B(D)/B(T) at the B locus, while the pure-chemotype plants are due to homozygosity at the B locus (either B(D)/B(D) or B(T)/B(T)). It is suggested that such codominance is due to the codification by the two alleles for different isoforms of the same synthase, having different specificity for the conversion of the common precursor cannabigerol into CBD or THC, respectively. The F(2) segregating groups were used in a bulk segregant analysis of the pooled DNAs for screening RAPD primers; three chemotype-associated markers are described, one of which has been transformed in a sequence-characterized amplified region (SCAR) marker and shows tight linkage to the chemotype and codominance.

Combining chemical genetics and proteomics to identify protein kinase substrates

Noah Dephoure — 2006-01-13T20:54:28-00:00

PNAS, Vol. 102, No. 50. (13 December 2005), pp. 17940-17945.

Phosphorylation is a ubiquitous protein modification important for regulating nearly every aspect of cellular biology. Protein kinases are highly conserved and constitute one of the largest gene families. Identifying the substrates of a kinase is essential for understanding its cellular role, but doing so remains a difficult task. We have developed a high-throughput method to identify substrates of yeast protein kinases that employs a collection of yeast strains each expressing a single epitope-tagged protein and a chemical genetic strategy that permits kinase reactions to be performed in native, whole-cell extracts. Using this method, we screened 4,250 strains expressing epitope-tagged proteins and identified 24 candidate substrates of the Pho85-Pcl1 cyclin-dependent kinase, including the known substrate Rvs167. The power of this method to identify true kinase substrates is strongly supported by functional overlap and colocalization of candidate substrates and the kinase, as well as by the specificity of Pho85-Pcl1 for some of the substrates compared with another Pho85-cyclin kinase complex. This method is readily adaptable to other yeast kinases.

Graph-theoretic methods for the analysis of chemical and biochemical networks. I. Multistability and oscillations in ordinary differential equation models

Maya Mincheva — 2007-07-31T15:53:31-00:00

Journal of Mathematical Biology, Vol. 55, No. 1. (16 July 2007), pp. 61-86.

Abstract A chemical mechanism is a model of a chemical reaction network consisting of a set of elementary reactions that express how molecules react with each other. In classical mass-action kinetics, a mechanism implies a set of ordinary differential equations (ODEs) which govern the time evolution of the concentrations. In this article, ODE models of chemical kinetics that have the potential for multiple positive equilibria or oscillations are studied. We begin by considering some methods of stability analysis based on the digraph of the Jacobian matrix. We then prove two theorems originally given by A. N. Ivanova which correlate the bifurcation structure of a mass-action model to the properties of a bipartite graph with nodes representing chemical species and reactions. We provide several examples of the application of these theorems.

Graph-theoretic methods for the analysis of chemical and biochemical networks. II. Oscillations in networks with delays

Maya Mincheva — 2007-07-31T15:53:01-00:00

Journal of Mathematical Biology, Vol. 55, No. 1. (16 July 2007), pp. 87-104.

Abstract Delay-differential equations are commonly used to model genetic regulatory systems with the delays representing transcription and translation times. Equations with delayed terms can also be used to represent other types of chemical processes. Here we analyze delayed mass-action systems, i.e. systems in which the rates of reaction are given by mass-action kinetics, but where the appearance of products may be delayed. Necessary conditions for delay-induced instability are presented in terms both of a directed graph (digraph) constructed from the Jacobian matrix of the corresponding ODE model and of a species-reaction bipartite graph which directly represents a chemical mechanism. Methods based on the bipartite graph are particularly convenient and powerful. The condition for a delay-induced instability in this case is the existence of a subgraph of the bipartite graph containing an odd number of cycles of which an odd number are negative.

Chemical Similarity Searching

P Willett — 2007-05-30T11:07:11-00:00

J. Chem. Inf. Model., Vol. 38, No. 6. (23 November 1998), pp. 983-996.

Abstract: This paper reviews the use of similarity searching in chemical databases. It begins by introducing the concept of similarity searching, differentiating it from the more common substructure searching, and then discusses the current generation of fragment-based measures that are used for searching chemical structure databases. The next sections focus upon two of the principal characteristics of a similarity measure: the coefficient that is used to quantify the degree of structural resemblance between pairs of molecules and the structural representations that are used to characterize molecules that are being compared in a similarity calculation. New types of similarity measure are then compared with current approaches, and examples are given of several applications that are related to similarity searching.

Comparing the chemical spaces of metabolites and available chemicals: models of metabolite-likeness

Gupta — 2007-06-07T16:52:54-00:00

Molecular Diversity, Vol. 11, No. 1. (February 2007), pp. 23-36.

Chemoinformatics Research at the University of Sheffield: A History and Citation Analysis

Neal Bishop — 2007-05-30T13:44:34-00:00

Journal of Information Science, Vol. 29, No. 4. (1 August 2003), pp. 249-267.

This paper reviews the work of the Chemoinformatics Research Group in the Department of Information Studies at the University of Sheffield, focusing particularly on the work carried out in the period 1985-2002. Four major research areas are discussed, these involving the development of methods for: substructure searching in databases of three-dimensional structures, including both rigid and flexible molecules; the representation and searching of the Markush structures that occur in chemical patents; similarity searching in databases of both two-dimensional and three-dimensional structures; and compound selection and the design of combinatorial libraries. An analysis of citations to 321 publications from the Group shows that it attracted a total of 3725 residual citations during the period 1980-2002. These citations appeared in 411 different journals, and involved 910 different citing organizations from 54 different countries, thus demonstrating the widespread impact of the Group's work. 10.1177/01655515030294003

A Fast Algorithm For Selecting Sets Of Dissimilar Molecules From Large Chemical Databases

John Holliday — 2007-05-30T13:41:28-00:00

Quantitative Structure-Activity Relationships, Vol. 14, No. 6. (1995), pp. 501-506.

Current algorithms for the selection of a set of n dissimilar molecules from a dataset of N molecules have an expected time complexity of O(n2N). This paper describes an improved algorithm that has an expected time complexity of O(nN) and that will identify exactly the same set of molecules as the normal algorithm if the cosine coefficient is used for the calculation of the inter-molecular (dis)similarities. The algorithm is applicable to any type of representation that characterises a molecule by a set of attribute values and to any procedure that involves calculating a sum of inter-molecular similarities. It is also both more effective and more efficient than our implementation of a genetic algorithm for the selection of maximally-dissimilar sets of molecules.

Molecular Similarity in Drug Design

PM Dean — 2005-04-26T13:04:48-00:00

(31 December 1899)

Similarity and Clustering in Chemical Information Systems (Chemometrics Series, No 12)

Peter Willett — 2005-04-26T13:30:22-00:00

(01 April 1987)

Combinatorial efficacy achieved through two-point blockade within a signaling pathway-a chemical genetic approach.

QW Fan — 2004-11-22T00:17:30-00:00

Cancer Res, Vol. 63, No. 24. (15 December 2003), pp. 8930-8938.

Whether the apparent efficacy of a specific kinase inhibitor is attributable solely to inhibition of its primary target, or to combined inhibition of additional unidentified kinases, is a critical issue in cancer therapy. We used a chemical genetic approach to generate a selective inhibitor of v-erbB [a transforming allele of epidermal growth factor receptor (EGFR)] and interrogated inhibition in known downstream signaling pathways. On the basis of this analysis, we hypothesized that dual inhibition of v-erbB and phosphatidylinositol 3' (PI3) kinases could show improved potency. We, therefore, used two different cell lines to examine the effects of v-erbB or EGFR inhibitors, in combination with PI3 kinase inhibitors, in mouse models for EGFR-driven cancers. When treated with NaPP1, v-erbB-as1-transformed fibroblasts showed cell-cycle arrest and decreased activity of Akt kinase. Inhibitors of v-erbB-as1 and of PI3 kinase showed enhanced efficacy in treating established 3T3:v-erbB-as1 tumor allografts. We extended these results to the human glioma cell line U87:MG transduced with DeltaEGFR, a tumor-derived activated allele, treating tumor-bearing mice with vehicle, the EGFR inhibitor ZD1839, LY294002, or ZD1839 plus LY294002. In human glioma xenografts, inhibition of EGFR cooperated similarly with inhibition of PI3 kinase. Our experiments provide a preclinical mechanistic basis for combining biologically based therapies directed against two targets within a complex signaling cascade.

A chemical genetic screen for direct v-Src substrates reveals ordered assembly of a retrograde signaling pathway.

K Shah — 2004-11-22T00:17:30-00:00

Chem Biol, Vol. 9, No. 1. (January 2002), pp. 35-47.

Using an ATP analog that is a specific substrate for an analog-specific allele of v-Src, we identified several novel cytoskeletal substrates that control actin assembly processes. A screen for less abundant v-Src substrates revealed the scaffolding protein Dok-1 as a direct substrate of v-Src. Further studies suggest that v-Src phosphorylation sites on Dok-1 are critical for its binding to RasGAP and Csk, negative regulators of Src signaling. This results in the downregulation of growth-promoting signals of the Src family kinases and the Ras pathway. Identification of the direct substrates of v-Src leads to a model for the precise order of assembly of a retrograde signaling pathway in v-Src-transformed cells and has provided new insight into the balance between those signals that promote cell transformation mediated by v-Src catalyzed tyrosine phosphorylation and those that inhibit it.

Butyltin concentrations along the Japanese coast from 1997 to 1999 monitored by Caprella spp. (Crustacea: Amphipoda).

I Takeuchi — 2006-07-29T02:27:34-00:00

Mar Environ Res, Vol. 57, No. 5. (June 2004), pp. 397-414.

The concentrations of butyltins along the Japanese coastline were investigated from 1997 to 1999, 7 to 9 years after implementation of legislation limiting the use of tributyltin (TBT) in Japan. Seawater was sampled at 0.5 m depth, and Caprella spp. were collected from Sargassum spp. and aquaculture facilities from 18 areas within four broad areas along the coastline of Japan, i.e., the Pacific coast of northern Japan, the coast along the Sea of Japan, Tokyo Bay and adjacent areas, and western Japan. Butyltins (MBT, DBT and TBT) were detected in 32 of the 63 seawater samples with average concentrations of 4.6 ng MBT/l, 4.5 ng DBT/l and 6.8 ng TBT/l, respectively. Butyltin concentrations in seawater from western Japan indicate "hot spots" even in unpopulated areas. Butyltins (MBT, DBT and TBT) were detected in all samples of Caprella spp., varying from 2.3 ng BTs /g wet wt in C. penantis R-type from Tobishima Island in the Sea of Japan to 464 ng BTs /g wet wt in C. decipiens Mayer from Amakusa, western Kyushu. The BT concentrations in Caprella spp. form western Japan were significantly higher than those from other areas, including Tokyo Bay and adjacent areas, where large scale industry and international ports are located. These results indicate that butyltin contamination still remains even in unpopulated areas after the regulation on TBT usage, and that the regulation governing TBT usage since 1990 has not been effective enough to concede recovery of shallow water ecosystems around Japan.

Ultrafast shape recognition to search compound databases for similar molecular shapes.

Pedro J Ballester — 2007-03-21T22:00:11-00:00

J Comput Chem (6 March 2007)

Finding a set of molecules, which closely resemble a given lead molecule, from a database containing potentially billions of chemical structures is an important but daunting problem. Similar molecular shapes are particularly important, given that in biology small organic molecules frequently act by binding into a defined and complex site on a macromolecule. Here, we present a new method for molecular shape comparison, named ultrafast shape recognition (USR), capable of screening billions of compounds for similar shapes using a single computer and without the need of aligning the molecules before testing for similarity. Despite its extremely fast comparison rate, USR will be shown to be highly accurate at describing, and hence comparing, molecular shapes. (c) 2007 Wiley Periodicals, Inc. J Comput Chem, 2007.

Gas measurement systems based on IEEE1451.2 standard

Antonio Pardo — 2008-05-07T08:07:50-00:00

Sensors and Actuators B: Chemical, Vol. 116, No. 1-2. (28 July 2006), pp. 11-16.

The design of electronic noses has a considerable dependence on the selected transducer set. There are many sensor technologies useful for be integrated in electronic noses, but every technology involves a dedicated electronics. In that sense, migration of the instrument to different sensor technologies usually involves a major redesign of the electronics and the software. The standard IEEE1451 can be a helpful tool to design smart electronic noses compatible with the possibility to use different sensors technologies without major redesigning efforts. In this work we present a solution for the development of electronic noses based on this standard and we have analyzed and studied its feasibility in this kind of systems.

Flexible tag microlab development: Gas sensors integration in RFID flexible tags for food logistic

Estefania Abad — 2008-05-07T07:57:20-00:00

Sensors and Actuators B: Chemical, Vol. 127, No. 1. (20 October 2007), pp. 2-7.

The enabling technologies for the development of a flexible tag microlab for food monitoring during the logistic chain will be presented. The realisation of the system includes the integration of physical and chemical sensors with Radio Frequency IDentification (RFID) communication capabilities. The first ISO 15693 compliant semi-active tag prototype, including low power control electronics, RFID antenna, commercial sensors, memory and a thin film battery, is shown together with the development of novel ultra-low power hotplates required for this application and the process, based on the use of anisotropic conductive adhesive (ACA) flip chip technology, for gas sensors integration onto flexible substrates.

sMOL Explorer: an open source, web-enabled database and exploration tool for Small MOLecules datasets.

Supawadee Ingsriswang — 2007-08-08T04:26:46-00:00

Bioinformatics (27 July 2007)

SUMMARY: sMOL Explorer is a 2D ligand-based computational tool that provides three major functionalities: data management, information retrieval and extraction, and statistical analysis and data mining through Web interface. With sMOL Explorer, users can create his/her ownpersonal databases by adding each small molecule via a drawing interface or uploading the data files from internal and external projects into the sMOL database. Then, the database can be browsed and queried with textual and structural similarity search. The molecule can also be submitted to search against external public databases including PubChem, KEGG, DrugBank and eMolecules. Moreover, users can easily access a variety of data mining tools from Weka and R packages to perform analysis including (1) finding the frequent substructure, (2) clustering the molecular fingerprints, (3) identifying and removing irrelevant attributes from the data, and (4) building the classification model of biological activity. AVAILABILITY: sMOL Explorer is an Open Source project and is freely available to all interested users at http://www.biotec.or.th/ISL/SMOL/. CONTACT: supawadee@biotec.or.th.

Autonomous artificial nanomotor powered by sunlight

Vincenzo Balzani — 2006-02-02T13:33:16-00:00

PNAS, Vol. 103, No. 5. (31 January 2006), pp. 1178-1183.

Light excitation powers the reversible shuttling movement of the ring component of a rotaxane between two stations located at a 1.3-nm distance on its dumbbell-shaped component. The photoinduced shuttling movement, which occurs in solution, is based on a "four-stroke" synchronized sequence of electronic and nuclear processes. At room temperature the deactivation time of the high-energy charge-transfer state obtained by light excitation is approx10 micros, and the time period required for the ring-displacement process is on the order of 100 micros. The rotaxane behaves as an autonomous linear motor and operates with a quantum efficiency up to approx12%. The investigated system is a unique example of an artificial linear nanomotor because it gathers together the following features: (i) it is powered by visible light (e.g., sunlight); (ii) it exhibits autonomous behavior, like motor proteins; (iii) it does not generate waste products; (iv) its operation can rely only on intramolecular processes, allowing in principle operation at the single-molecule level; (v) it can be driven at a frequency of 1 kHz; (vi) it works in mild environmental conditions (i.e., fluid solution at ambient temperature); and (vii) it is stable for at least 103 cycles.

Genomics and proteomics From genes to function: advances in applications of chemical and systems biology.

Matthew Bogyo — 2007-01-31T09:29:36-00:00

Curr Opin Chem Biol (9 January 2007)

The chemical abstract machine

Gerard Berry — 2006-11-23T10:58:38-00:00

(1990), pp. 81-94.

Assessing the ability of chemical similarity measures to discriminate between active and inactive compounds

John Delaney — 2007-04-14T13:10:26-00:00

Molecular Diversity, Vol. 1, No. 4. (1996), pp. 217-222.

The mechanism distinguishability problem in biochemical kinetics: The single-enzyme, single-substrate reaction as a case study

Santiago Schnell — 2006-10-20T23:26:53-00:00

Comptes Rendus Biologies, Vol. 329, No. 1. (January 2006), pp. 51-61.

A theoretical analysis of the distinguishability problem of two rival models of the single enzyme-single substrate reaction, the Michaelis-Menten and Henri mechanisms, is presented. We also outline a general approach for analysing the structural indistinguishability between two mechanisms. The approach involves constructing, if possible, a smooth mapping between the two candidate models. Evans et al. [N.D. Evans, M.J. Chappell, M.J. Chapman, K.R. Godfrey, Structural indistinguishability between uncontrolled (autonomous) nonlinear analytic systems, Automatica 40 (2004) 1947-1953] have shown that if, in addition, either of the mechanisms satisfies a particular criterion then such a transformation always exists when the models are indistinguishable from their experimentally observable outputs. The approach is applied to the single enzyme-single substrate reaction mechanism. In principle, mechanisms can be distinguished using this analysis, but we show that our ability to distinguish mechanistic models depends both on the precise measurements made, and on our knowledge of the system prior to performing the kinetics experiments. To cite this article: S. Schnell et al., C. R. Biologies 329 (2006).

Untitled

2006-05-01T08:00:49-00:00

Concentrations and source variations of n-alkanes in a 21 m ice core and snow samples at Belukha glacier, Russian Altai mountains

Miyake — 2007-01-30T11:43:09-00:00

Annals of Glaciology, Vol. 43, No. 1. (September 2006), pp. 142-147.

The antibiotic resistome: the nexus of chemical and genetic diversity

Gerard Wright — 2007-02-17T20:57:35-00:00

Nature Reviews Microbiology, Vol. 5, No. 3., pp. 175-186.

Optical Nanosensors for Chemical Analysis inside Single Living Cells. 2. Sensors for pH and Calcium and the Intracellular Application of PEBBLE Sensors

HA Clark — 2007-07-29T20:29:12-00:00

Anal. Chem., Vol. 71, No. 21. (1 November 1999), pp. 4837-4843.

Abstract: Optical nanosensors, or PEBBLEs (probes encapsulated by biologically localized embedding), have been produced for intracellular measurements of pH and calcium. Five varieties of pH-sensitive sensors and three different calcium-selective sensors are presented and discussed. Each sensor combines an ion-selective fluorescent indicator and an ion-insensitive internal standard entrapped within an acrylamide polymeric matrix. Calibrations and linear ranges are presented for each sensor. The photobleaching of dyes incorporated into PEBBLEs is comparable to that of the respective free dye that is incorporated within the matrix. These PEBBLE sensors are fully reversible over many measurements. The leaching of fluorescent indicator from the polymer is less than 50% over a 48-h period (note that a typical application time is only a few hours). The PEBBLE sensors have also been applied to intracellular analysis of the calcium flux in the cytoplasm of neural cells during the mitochondrial permeability transition. Specifically, a distinct difference is noted between cells of different types (astrocyte vs neuron-derived cells) with respect to their response to the toxicant m-dinitrobenzene (DNB). Use of PEBBLE sensors permits the quantitative discrimination of subtle differences between the ability of human SY5Y neuroblastoma and C6 glioma to respond to challenge with DNB. Specifically, measurement of intracellular calcium, the precursor to cell death, has been achieved.

Optochemical Nanosensors and Subcellular Applications in Living Cells

Heather Clark — 2007-07-29T20:25:48-00:00

Microchimica Acta, Vol. 131, No. 1. (24 June 1999), pp. 121-128.

What may be the smallest anthropogenic devices to date, spherical sensors (wireless and fiberless) with radii as small as 10 nm have been produced. This class of optochemical PEBBLE (Probe Encapsulated By Biologically Localized Embedding) sensors covers a wide range of analytes (pH, calcium, oxygen and potassium included here) with excellent spatial, temporal and chemical resolution. Examples of such sensors for the monitoring of intracellular analytes are given. Methods, such as pico-injection, liposomal delivery and gene gun bombardment, are used to inject PEBBLE sensors into single cells. These PEBBLEs have caused minimal perturbation when delivered and operated inside single mammalian cells, such as human neuroblastoma, mouse oocytes or rat alveolar macrophage.

Optical trapping-chemical analysis of single microparticles in solution

N Kitamura — 2004-12-28T16:59:23-00:00

Journal of Photochemistry and Photobiology, C: Photochemistry Reviews, Vol. 4, No. 3. (15 December 2003), pp. 227-247.

Photoexcitation-based nano-explorers: Chemical analysis inside live cells and photodynamic therapy

H Xu — 2007-03-08T23:41:21-00:00

Isr. J. Chem., Vol. 44, No. 1-3. (2004), pp. 317-337.

PEBBLEs (Probes Encapsulated By Biologically Localized Embedding) are submicron-sized optical sensors designed specifically for minimally invasive analyte monitoring in viable single cells, with applications for real-time analysis of drug, toxin, and environmental effects on cell function. PEBBLE nanosensor is a general term that describes a family of matrices and nano-fabrication techniques used to miniaturize many existing optical sensing technologies. The main classes of PEBBLE nanosensors are based on matrices of cross-linked polyacrylamide, cross-linked poly(decyl methacrylate), and sol-gel silica. These matrices have been used to fabricate sensors for H+, Ca2+, K+, Na+, Mg2+, Zn 2+, Cu2+, Cl-, O2, NO, and glucose that range from 20 nm to 600 nm in diameter. A number of delivery techniques have been used successfully to deliver PEBBLE nanosensors into mouse oocytes, rat alveolar macrophages, rat C6-glioma, and human neuroblastoma cells. PEBBLEs with several newly emerging directions in design and applications, going from intracellular imaging to in vivo actuating and targeting, are also described. They include photonic, magnetic, and stochastic control and modulation of photo-excitation, and also targeted nano-platforms for photodynamic therapy of brain cancers, as well as contrast enhancement of the MRI for monitoring such therapy.

Features of gold having micrometer to centimeter dimensions can be formed through a combination of stamping with an elastomeric stamp and an alkanethiol “ink” followed by chemical etching

A Kumar — 2007-09-03T02:09:26-00:00

Applied Physics Letters, Vol. 63 (October 1993), pp. 2002-2004.

Not Available

Light-directed, spatially addressable parallel chemical synthesis.

SP Fodor — 2006-11-14T00:56:52-00:00

Science, Vol. 251, No. 4995. (15 February 1991), pp. 767-773.

Solid-phase chemistry, photolabile protecting groups, and photolithography have been combined to achieve light-directed, spatially addressable parallel chemical synthesis to yield a highly diverse set of chemical products. Binary masking, one of many possible combinatorial synthesis strategies, yields 2n compounds in n chemical steps. An array of 1024 peptides was synthesized in ten steps, and its interaction with a monoclonal antibody was assayed by epifluorescence microscopy. High-density arrays formed by light-directed synthesis are potentially rich sources of chemical diversity for discovering new ligands that bind to biological receptors and for elucidating principles governing molecular interactions. The generality of this approach is illustrated by the light-directed synthesis of a dinucleotide. Spatially directed synthesis of complex compounds could also be used for microfabrication of devices.

Efficient Exact Stochastic Simulation of Chemical Systems with Many Species and Many Channels

MA Gibson — 2006-08-01T23:16:10-00:00

J. Phys. Chem. A, Vol. 104, No. 9. (9 March 2000), pp. 1876-1889.

Chemical polishing of LSO crystals to increase light output

R Slates — 2008-04-04T17:05:23-00:00

Nuclear Science, IEEE Transactions on, Vol. 47, No. 3. (2000), pp. 1018-1023.

Surface treatment of scintillators is critical for light collection from narrow rectangular crystals. The authors investigated chemical polishing which is less labor intensive and expensive than hand and machine polishing. They used phosphoric acid to chemically polish LSO crystals at 110°C, 150°C and 190°C, and compared these with unpolished and mechanically polished crystals. Groups of five 2×2×10 mm crystals were etched for different times at each temperature. Weight loss, light output and energy resolution were measured as a function of treatment time and temperature. The authors found that chemical polishing can increase light output by 250% relative to unpolished crystals and by 16% relative to mechanically polished crystals. The energy resolution was relatively independent of surface treatment, with values of between 14 and 16%. The rate of loss of LSO was 0.02%/min at 110°C, 0.1%/min at 150°C and 0.36%/min at 190°C. Maximum light output occurred when 5-10% of the LSO was removed. The crystals were also imaged using scanning electron microscopy and the surface roughness quantitatively assessed by using a profilometer. These measurements helped to clarify the effect of acid polishing on the surface of the scintillator. In summary, chemical polishing appears to be a convenient and effective method for improving light output from small LSO crystals

Produktdesign - Beschleunigte Entwicklung von Produkten durch Einbeziehung des Kunden

W Rähse — 2007-05-16T12:25:38-00:00

Chemie Ingenieur Technik, Vol. 76, No. 3. (2004), pp. 220-231.

Im Zuge der Globalisierung erfolgte in den 90er Jahren eine Besinnung der chemischen Industrie auf ihre Kernkompetenz: die Einführung innovativer Produkte. Zur effektiven Entwicklung wurden in einigen Unternehmen die Organisations- und Projektstrukturen geändert. Heute steuert ein Team aus Produkt- und Verfahrensentwicklern gemeinsam mit dem Marketing die Einzelschritte der Produktentwicklung unter Einbeziehung interner und externer Fachleute. Die Kunden werden von der Produktidee bis zum Markteintritt an der Entwicklung beteiligt, zum einen zur zielgerichteten, beschleunigten Abwicklung und zum anderen zur Minimierung des Floprisikos. Die Konkretisierung neuer Produktideen erfolgt durch Aufzeigen der chemischen und der technischen Möglichkeiten zur Umsetzung, bevor eine Bewertung des Vorschlages erfolgt. Anhand des Innovations-&ldquor;Thermometers&rdquor; kann die Innovationshöhe eingeordnet werden, mit Hilfe des &ldquor;Barometers&rdquor; lassen sich die Marktchancen von Ideen abschätzen. Die Produktentwicklung muss bei Marktneuheiten zur Sicherung eines Markterfolgs sehr schnell erfolgen. Eine beschleunigte Produktentwicklung erfordert die Erfüllung von zehn Voraussetzungen, die im Detail erklärt werden. Am Beispiel fester &ldquor;Waschmittel&rdquor; wird die Ermittlung von Kundenbedürfnissen diskutiert. Zur Beeinflussung des Partikeldesigns, insbesondere zur Verbesserung der Ästhetik, existiert eine Reihe interessanter, in den Herstellprozess integrierbarer Technologien.

Approaches to Measure Chemical Similarity - a Review

Nina Nikolova — 2005-04-18T12:45:55-00:00

QSAR & Combinatorial Science, Vol. 22, No. 9-10. (23 January 2004), pp. 1006-1026.

Although the concept of similarity is a convenient for humans, a formal definition of similarity between chemical compounds is needed to enable automatic decision-making. The objective of similarity measures in toxicology and drug design is to allow assessment of chemical activities. The ideal similarity measure should be relevant to the activity of interest. The relevance could be established by exploiting the knowledge about fundamental chemical and biological processes responsible for the activity. Unfortunately, this knowledge is rarely available and therefore different approximations have been developed based on similarity between structures or descriptor values. Various methods are reviewed, ranging from two-dimensional, three-dimensional and field approaches to recent methods based on <IMG SRC="/giflibrary/12/ldquo.gif" BORDER="0">Atoms in Molecules<IMG SRC="/giflibrary/12/rdquo.gif" BORDER="0"> theory. All these methods attempt to describe chemical compounds by a set of numerical values and define some means for comparison between them. The review provides analysis of potential pitfalls of this methodology - loss of information in the representations of molecular structures - the relevance of a particular representation and chosen similarity measure to the activity. A brief review of known methods for descriptor selection is also provided. The popular <IMG SRC="/giflibrary/12/ldquo.gif" BORDER="0">neighborhood behavior<IMG SRC="/giflibrary/12/rdquo.gif" BORDER="0"> principle is criticized, since proximity with respect to descriptors does not necessarily mean proximity with respect to activity. Structural similarity should also be used with care, as it does not always imply similar activity, as shown by examples. We remind that similarity measures and classification techniques based on distances rely on certain data distribution assumptions. If these assumptions are not satisfied for a given dataset, the results could be misleading. A discussion on similarity in descriptor space in the context of applicability domain assessment of QSAR models is also provided. Finally, it is shown that descriptor based similarity analysis is prone to errors if the relationship between the activity and the descriptors has not been previously established. A justification for the usage of a particular similarity measure should be provided for every specific activity by expert knowledge or derived by data modeling techniques.

How many leads from HTS?

Roger Lahana — 2007-01-24T02:02:17-00:00

Drug Discovery Today, Vol. 4, No. 10. (1 October 1999), pp. 447-448.

The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease.

J Lamb — 2006-10-02T08:35:35-00:00

Science, Vol. 313, No. 5795. (29 September 2006), pp. 1929-1935.

To pursue a systematic approach to the discovery of functional connections among diseases, genetic perturbation, and drug action, we have created the first installment of a reference collection of gene-expression profiles from cultured human cells treated with bioactive small molecules, together with pattern-matching software to mine these data. We demonstrate that this "Connectivity Map" resource can be used to find connections among small molecules sharing a mechanism of action, chemicals and physiological processes, and diseases and drugs. These results indicate the feasibility of the approach and suggest the value of a large-scale community Connectivity Map project.

Single molecule transcription profiling with AFM

Jason Reed — 2008-06-29T23:40:49-00:00

Nanotechnology, Vol. 18, No. 4. (2007), 044032.

Established techniques for global gene expression profiling, such as microarrays, face fundamental sensitivity constraints. Due to greatly increasing interest in examining minute samples from micro-dissected tissues, including single cells, unorthodox approaches, including molecular nanotechnologies, are being explored in this application. Here, we examine the use of single molecule, ordered restriction mapping, combined with AFM, to measure gene transcription levels from very low abundance samples. We frame the problem mathematically, using coding theory, and present an analysis of the critical error sources that may serve as a guide to designing future studies. We follow with experiments detailing the construction of high density, single molecule, ordered restriction maps from plasmids and from cDNA molecules, using two different enzymes, a result not previously reported. We discuss these results in the context of our calculations.

Chemical genetics: tailoring tools for cell biology.

TU Mayer — 2006-08-06T19:31:01-00:00

Trends Cell Biol, Vol. 13, No. 5. (May 2003), pp. 270-277.

Chemical genetics is a research approach that uses small molecules as probes to study protein functions in cells or whole organisms. Here, I review the parallels between classical genetic and chemical-genetic approaches and discuss the merits of small molecules to dissect dynamic cellular processes. I then consider the pros and cons of different screening approaches and specify strategies aimed at identifying and validating cellular target proteins. Finally, I highlight the impact of chemical genetics on our current understanding of cell biology and its potential for the future.

Efficient syntheses of the keto-carotenoids canthaxanthin, astaxanthin, and astacene.

S Choi — 2007-09-26T19:21:24-00:00

J Org Chem, Vol. 70, No. 8. (15 April 2005), pp. 3328-3331.

Three keto-carotenoids were prepared by the oxidation of the stable C(40) trisulfone 6, which has been used as the key compound in our beta-carotene synthesis. The first allylic oxidation to the unsaturated ketone and the second oxidation to the alpha-hydroxyketone produced the C(40) trisulfones 7 and 10, respectively. The Ramberg-Backlund reaction of the oxidized C(40) trisulfone was efficiently effected by the use of a mild base, NaOMe, in the presence of CCl(4) as a halogenating agent to give the C(40) disulfones 8 and 11. Base-promoted dehydrosulfonation reaction of the disulfone compounds produced the fully conjugated polyenes of canthaxanthin (1), astaxanthin (2), and astacene (3).