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At least 649 records · Page 36Linked to original sources
PubMed2005

Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation.

We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC(50) 35 microM) identified using X-ray crystallographic screening of p38alpha MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.

Aminopyridines↗
PubMed2006

Structure-based optimization of azole antifungal agents by CoMFA, CoMSIA, and molecular docking.

In a continuing effort to develop highly potent azole antifungal agents, the three-dimensional quantitative structure-activity relationship methods, CoMFA and CoMSIA, were applied using a set of novel azole antifungal compounds. The binding mode of the compounds at the active site of lanosterol 14alpha-demethylase was further explored using the flexible docking method. Various hydrophobic, van der Waals, pi-pi stacking, and hydrogen bonding interactions were observed between the azoles and the enzyme. Based on results from the molecular modeling, a receptor-based pharmacophore model was established to guide the rational optimization of the azole antifungal agents. Thus, a total of 57 novel azoles were designed and synthesized by a three-step optimization process. In vitro antifungal assay revealed that the antifungal activities of these novel azoles were greatly improved, which confirmed the reliability of the model from molecular modeling.

Antifungal Agents↗
PubMed2006

Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- {[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity.

The discovery of novel acyclic amide cannabinoid-1 receptor inverse agonists is described. They are potent, selective, orally bioavailable, and active in rodent models of food intake and body weight reduction. A major focus of the optimization process was to increase in vivo efficacy and to reduce the potential for formation of reactive metabolites. These efforts led to the identification of compound 48 for development as a clinical candidate for the treatment of obesity.

Animals↗
PubMed1999

Three-dimensional quantitative structure-activity relationship analyses using comparative molecular field analysis and comparative molecular similarity indices analysis to elucidate selectivity differences of inhibitors binding to trypsin, thrombin, and factor Xa.

Three-dimensional quantitative structure-activity relationship (3D QSAR) methods were applied using a training set of 72 inhibitors of the benzamidine type with respect to their binding affinities (Ki values) toward thrombin, trypsin, and factor Xa to yield statistically reliable models of good predictive power. Two methods were compared: the widely used comparative molecular field analysis (CoMFA) and the recently reported CoMSIA approach (comparative molecular similarity indices analysis). CoMSIA produced significantly better results for all correlations. Furthermore, in contrast to CoMFA, CoMSIA is not sensitive to changes in orientation of the superimposed molecules in the lattice. The correlation results obtained by CoMSIA were graphically interpreted in terms of field contribution maps allowing physicochemical properties relevant for binding to be easily mapped back onto molecular structures. The advantage of this feature is demonstrated using the maps to design new molecules. Finally, the CoMSIA method was applied to elucidate structural features among ligands which are responsible for affinity differences toward thrombin and trypsin. These selectivity-determining features were interpreted graphically in terms of spatial regions responsible for affinity discrimination. Such indicators are highly informative for the lead optimization process with respect to selectivity enhancement.

Binding Sites↗
PubMed2000

Multivariate data analysis using D-optimal designs, partial least squares, and response surface modeling: A directional approach for the analysis of farnesyltransferase inhibitors.

We have investigated the combined use of partial least squares (PLS) and statistical design principles in principal property space (PP-space), derived from principal component analysis (PCA), to analyze farnesyltransferase inhibitors in order to identify "activity trends" (an approach we call a "directional" approach) and quantitative structure-activity relationships (QSAR) for a congeneric series of inhibitors: the benzo[f]perhydroisoindole (BPHI) series. Trends observed in the PCA showed that the descriptors used were relevant to describe our structural data set by clearly identifying two well-defined structural subclasses of inhibitors. D-Optimal design techniques allowed us to define a training set for PLS study in PP-space. Models were derived for each biological assay under evaluation: the in vitro Ki-Ras and cellular HCT116 tests. Each of these assay-based sets was subdivided once more into two subsets according to two structural classes in this BPHI series as revealed by the PCA model. The response surface modeling (RSM) methodology was used for each subset, and the corresponding RSM plots helped us identify "activity trends" exploited to guide further analogue design. For more precise activity predictions more refined PLS models on constrained PP-spaces were developed for each subset. This approach was validated with predicted sets and demonstrates that useful information can be extracted from just a few very informative and representative compounds. Finally, we also showed the potential use of such a strategy at an early stage of an optimization process to extract the first "activity trends" that might support decision making and guide medicinal chemists in the initial design of new analogues and/or lead followup libraries.

Alkyl and Aryl Transferases↗
PubMed2000

Copper(I)-assisted mild and convenient synthesis of new Se--N heterocycles: access to a promising class of GPx mimics.

Benzisoselenazolines 15 and benzisoselenazines 21, designed as low molecular weight mimics of glutathione peroxidases, were synthesized for the first time. Starting from amines 13 and 14, a smooth introduction of selenium in nonactivated aryl bromides using KSeCN in the presence of CuI was developed. An equimolar quantity of CuI and the presence of Et(3)N as a base are necessary to achieve a complete conversion of the starting material. The reaction is feasible in various solvents such as DMF, acetonitrile, and THF. The desired new Se-N heterocycles 15 and 21 were isolated under optimized conditions in yields of 82 and 68%, respectively. Experiments have been conducted with various copper(I) and copper(II) salts, a chloroamine 17, an aryl bromide 18, and an N-acylated amine 19 to show the scope and the limitations of this method. The previously unknown sulfur analogues 20 and 22 have been synthesized in moderate yields using a slightly modified procedure. Finally, a mechanistic scheme has been proposed to discuss some interesting findings, which were obtained during the optimization process of this new introduction of selenium.

Copper↗
PubMed2006

Defect disorder of titanium dioxide.

The present work derived defect disorder diagram representing the effect of oxygen activity on the concentration of both ionic and electronic defects for undoped TiO2. This diagram was determined using the equilibrium constants derived in the present work, including (i) the intrinsic electronic equilibrium constant, (ii) the equilibrium constant for the formation of oxygen vacancies, and (iii) equilibrium constant for the formation of titanium vacancies. These equilibrium constants are consistent with three properties determined independently, including: electrical conductivity, thermoelectric power and change of mass determined by thermogravimetry. The derived defect disorder diagram may be used for tailoring semiconducting properties of TiO2 that are desired for specific applications through the selection of optimized processing conditions.

Journal Article↗
PubMed2005

Ultraviolet electroluminescence from ZnO/polymer heterojunction light-emitting diodes.

We report ultraviolet electroluminescence at 390 nm from diode structures consisting of electrodeposited ZnO nanorods sandwiched between a transparent SnO(2) film and a p-type conducting polymer. The nanorods are embedded in an insulating polystyrene layer. ZnO deposition occurs at 90 degrees C and produces vertically oriented nanorods with very high uniformity over areas of approximately 20 cm(2). Electron diffraction shows the nanorods to be single crystalline wurtzite ZnO. As-grown films show a broad electroluminescence band over the visible spectrum. Annealing at moderate temperatures (T = 300 degrees C) increases the emission and strongly raises the excitonic contribution. Optimally processed films show a narrow ultraviolet electroluminescence line at approximately 390 nm.

Journal Article↗
PubMed2006

Comparative assessment of technologies for extraction of artemisinin.

This paper describes results of a multiobjective comparative assessment of several established and emerging technologies for extraction of a natural antimalarial substance, artemisinin. Extractions by hexane, supercritical carbon dioxide, hydrofluorocarbon HFC-134a, ionic liquids, and ethanol were considered. Hexane extraction is an established technology and appears to be the most cost-effective. However, it is characterized by lower rates and efficiency of extraction than all other considered techniques and is also worse in terms of safety and environmental impact. Similarly, EtOH extraction was found to be worse than hexane in all assessment parameters. The new technologies (scCO2, HFC, and ILs) are based on nonflammable solvents and are characterized by faster extraction cycles and more complete extraction of the useful substances and enable continuous extraction processes with reduced solvent inventory. Ionic liquid and HFC-134a technologies show considerable promise and should be able to compete with hexane extraction in terms of cost-effectiveness following due process optimization. New technologies are also considerably safer (no risk of explosions, low toxicity) and greener (having a lower environmental impact in use, potential for biodegradability after use). The methodology of comparative assessment of established and emerging technologies is discussed.

Antimalarials↗
PubMed2000

De novo design of molecular architectures by evolutionary assembly of drug-derived building blocks.

An evolutionary algorithm was developed for fragment-based de novo design of molecules (TOPAS, TOPology-Assigning System). This stochastic method aims at generating a novel molecular structure mimicking a template structure. A set of approximately 25,000 fragment structures serves as the building block supply, which were obtained by a straightforward fragmentation procedure applied to 36,000 known drugs. Eleven reaction schemes were implemented for both fragmentation and building block assembly. This combination of drug-derived building blocks and a restricted set of reaction schemes proved to be a key for the automatic development of novel, synthetically tractable structures. In a cyclic optimization process, molecular architectures were generated from a parent structure by virtual synthesis, and the best structure of a generation was selected as the parent for the subsequent TOPAS cycle. Similarity measures were used to define 'fitness', based on 2D-structural similarity or topological pharmacophore distance between the template molecule and the variants. The concept of varying library 'diversity' during a design process was consequently implemented by using adaptive variant distributions. The efficiency of the design algorithm was demonstrated for the de novo construction of potential thrombin inhibitors mimicking peptide and non-peptide template structures.

Algorithms↗
PubMed1998

Simulation and parameter estimation study of a simple neuronal model of rhythm generation: role of NMDA and non-NMDA receptors.

Simple neural network models of the Xenopus embryo swimming CPG, based on the one originally developed by Roberts and Tunstall (1990), were used to investigate the role of the voltage-dependent N-methyl-D-aspartate (NMDA) receptor channels, in conjunction with faster non-NMDA components of synaptic excitation, in rhythm generation. The voltage-dependent NMDA current "follows" the membrane potential, leading to a postinhibitory rebound that is more efficient than one without voltage dependency and allows neurons to fire more than one action potential per cycle. Furthermore, the model demonstrated limited rhythmic activity in the absence of synaptic inhibition, supporting the hypothesis that the NMDA channels provide a basic mechanism for rhythmicity. However, the rhythmic properties induced by the NMDA current were observed only when there was moderate activation of the non-NMDA synaptic channels, suggesting a modulatory role for this component. The simulations also show that the voltage dependency of the NMDA conductance, as well as the fast non-NMDA current, stabilizes the alternation pattern versus synchrony. To verify that these effects and their implications on the mechanism of swimming and transition to other types of activity take place in the real preparation, constraints on parameter values have to be specified. A method to estimate synaptic parameters was tested with generated data. It is shown that a global analysis, based on multiple iterations of the optimization process (Foster et al., 1993), gives a better understanding of the parameter subspace describing network activity than a standard fit with a sensitivity analysis for an individual solution.

Animals↗
PubMed2001

Noninvasive localization of electromagnetic epileptic activity. I. Method descriptions and simulations.

This paper considers the solution of the bioelectromagnetic inverse problem with particular emphasis on focal compact sources that are likely to arise in epileptic data. Two linear inverse methods are proposed and evaluated in simulations. The first method belongs to the class of distributed inverse solutions, capable of dealing with multiple simultaneously active sources. This solution is based on a Local Auto Regressive Average (LAURA) model. Since no assumption is made about the number of activated sources, this approach can be applied to data with multiple sources. The second method, EPIFOCUS, assumes that there is only a single focal source. However, in contrast to the single dipole model, it allows the source to have a spatial extent beyond a single point and avoids the non-linear optimization process required by dipole fitting. The performance of both methods is evaluated with synthetic data in noisy and noise free conditions. The simulation results demonstrate that LAURA and EPIFOCUS increase the number of sources retrieved with zero dipole localization error and produce lower maximum error and lower average error compared to Minimum Norm, Weighted Minimum Norm and Minimum Laplacian (LORETA). The results show that EPIFOCUS is a robust and powerful tool to localize focal sources. Alternatives to localize data generated by multiple sources are discussed. A companion paper (Lantz et al. 2001, this issue) illustrates the application of LAURA and EPIFOCUS to the analysis of interictal data in epileptic patients.

Artifacts↗
PubMed2001

CoMFA and CoMSIA 3D-quantitative structure-activity relationship model on benzodiazepine derivatives, inhibitors of phosphodiesterase IV.

Recently, we reported structurally novel PDE4 inhibitors based on 1,4-benzodiazepine derivatives. The main interest in developing bezodiazepine-based PDE4 inhibitors is in their lack of adverse effects of emesis with respect to rolipram-like compounds. A large effort has thus been made toward the structural optimization of this series. In the absence of structural information on the inhibitor binding mode into the PDE4 active site, 2D-QSAR (H-QSAR) and two 3D-QSAR (CoMFA and CoMSIA) methods were applied to improve our understanding of the molecular mechanism controlling the PDE4 affinity of the benzodiazepine derivatives. As expected, the CoMSIA 3D contour maps have provided more information on the benzodiazepine interaction mode with the PDE4 active site whereas CoMFA has built the best tool for activity prediction. The 2D pharmacophoric model derived from CoMSIA fields is consistent with the crystal structure of the PDE4 active site reported recently. The combination of the 2D and 3D-QSAR models was used not only to predict new compounds from the structural optimization process, but also to screen a large library of bezodiazepine derivatives.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2004

Improving the monitoring of methanol concentration during high cell density fermentation of Pichia pastoris.

The Pichia pastoris expression system is widely used for the production of recombinant proteins. A simple and efficient experimental set-up allowing on-line monitoring of the methanol concentration during the fermentation of P. pastoris based on the detection of the methanol vapor concentration in the exhaust air from fermenter by a tin dioxide (SnO2) semiconductor sensor is described. An experimental procedure to allow precise calibration of the system and to reduce methanol sensor's interferences (>95% reduction) are also presented and discussed. Accuracy and measurement error were estimated about 0.05 g x l(-1) and 6%, respectively. The efficient monitoring of methanol will help to advanced control of recombinant protein production and process optimization.

Bioreactors↗
PubMed2001

Stronger suboptimal than optimal affective priming?

The finding of stronger affective priming in less conscious (suboptimal) conditions than in fully conscious (optimal) conditions (S. T. Murphy & R. B. Zajonc, 1993) is theoretically important because it contradicts notions that emotions are primarily reflected by conscious states. In 2 experiments, this pattern of results was obtained. Happy and angry faces were presented both optimally and suboptimally and were masked by unknown ideographs. In Experiment 1, instructions for the conscious and less conscious affective priming conditions were matched, and affective ratings of ideographs were determined. In Experiment 2, a more implicit affective measure (facial electromyography of musculus zygomaticus major and musculus corrugator supercilii) served as the dependent variable. Stronger suboptimal than optimal affective priming was found in both experiments. It is concluded that stronger suboptimal than optimal processing is characteristic for affective processing and that it can also be found when instructions are matched and when a more implicit measure is assessed.

Adolescent↗
PubMed1996

Encapsulated cell technology.

The potential therapeutic applications of encapsulated cells are enormous. In the US alone, it has been estimated that nearly half-a-trillion dollars are spent each year to care for patients who suffer tissue loss or dysfunction. Over 6 million patients suffer from neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, over 14 million patients suffer from diabetes, and millions more from liver failure, hemophilia, and other diseases caused by the loss of specific vital cellular functions. It appears likely that by the end of the decade clinical trials of encapsulated cells to treat many of these diseases will become a reality. The Food and Drug Administration has already authorized studies to evaluate the safety and biological activity of several types of systems. A number of issues will have to be addressed, including the sourcing of raw materials, the design and building of manufacturing facilities, the scale-up and optimization process, storage and distribution of the product, and quality control.

Animals↗
PubMed2006

GM130 and GRASP65-dependent lateral cisternal fusion allows uniform Golgi-enzyme distribution.

The mammalian Golgi apparatus exists as stacks of cisternae that are laterally linked to form a continuous membrane ribbon, but neither the molecular requirements for, nor the purpose of, Golgi ribbon formation are known. Here, we demonstrate that ribbon formation is mediated by specific membrane-fusion events that occur during Golgi assembly, and require the Golgi proteins GM130 and GRASP65. Furthermore, these GM130 and GRASP65-dependent lateral cisternal-fusion reactions are necessary to achieve uniform distribution of enzymes in the Golgi ribbon. The membrane continuity created by ribbon formation facilitates optimal processing conditions in the biosynthetic pathway.

Autoantigens↗