Three-dimensional quantitative structure-activity relationships for a large series of potent antitubercular agents

Comparative molecular field analysis (CoMFA) studies were conducted on a series of 100 isoniazid derivatives as anti-tuberculosis agents using two receptor-independent structural data set alignment strategies: (1) rigid-body fit, and (2) pharmacophore-based. Significant cross-validated correlation coefficients were obtained (CoMFA(1), q(2) = 0,75 and CoMFA(2), q(2) = 0.74), indicating the potential of the models for untested compounds. The models were then used to predict the inhibitory potency of 20 test set compounds that were not included in the training set, and the predicted values were in good agreement with the experimental results.

Natural products biological screening and ligand-based virtual screening for the discovery of new antileishmanial agents

In the course of our research program to discover novel antileishmanial agents, a biological screening of natural products against Leishmania major promastigotes allowed the identification of a furoquinoline alkaloid (1) and a furanocoumarin (2) as new hits. Subsequently, an integrated ligand-based virtual screening approach was employed to search for new antileishmanial compounds using these naturally occurring molecules as templates. Fourteen out of 40 compounds selected from a database of about 800,000 compounds (extracted from ZINC, a free database for virtual screening) were experimentally confirmed to possess significant in vitro antileishmanial properties. The application of ligand-based virtual screening as a complementary approach to experimental natural product screening was a useful strategy to facilitate the identification of new promising lead candidates.

Classical and fragment-based hologram structure-activity relationships for a series of analgesic cyclic imides

Cyclic imides have been widely employed in drug design research due to their multiple pharmacological and biological properties. In the present study, two-dimensional quantitative structure-activity relationship (2D QSAR) studies were conducted on a series of potent analgesic cyclic imides using both classical and hologram QSAR (HQSAR) methods, yielding significant statistical models (classical QSAR, q(2) = 0.80; HQSAR, q(2) = 0.84). The models were then used to evaluate an external data test, and the predicted values were in good agreement with the experimental results, indicating their consistency for untested compounds.

Normalization procedure for relaxation studies in NMR quantum information processing

NMR quantum information processing studies rely on the reconstruction of the density matrix representing the so-called pseudo-pure states (PPS). An initially pure part of a PPS state undergoes unitary and non-unitary (relaxation) transformations during a computation process, causing a ""loss of purity"" until the equilibrium is reached. Besides, upon relaxation, the nuclear polarization varies in time, a fact which must be taken into account when comparing density matrices at different instants. Attempting to use time-fixed normalization procedures when relaxation is present, leads to various anomalies on matrices populations. On this paper we propose a method which takes into account the time-dependence of the normalization factor. From a generic form for the deviation density matrix an expression for the relaxing initial pure state is deduced. The method is exemplified with an experiment of relaxation of the concurrence of a pseudo-entangled state, which exhibits the phenomenon of sudden death, and the relaxation of the Wigner function of a pseudo-cat state.

The stability and aggregation properties of the GTPase domain from human SEPT4

The septins are a family of conserved proteins involved in cytokinesis and cortical organization. An increasing amount of data implicates different septins in diverse pathological conditions including neurodegenerative disorders, neoplasia and infections. Human SEPT4 is a member of this family and its tissue-specific ectopic expression profile in colorectal and urologic cancer makes it a useful diagnostic biomarker. Thermal unfolding of the GTPase domain of SEPT4 (SEPT4-G) revealed an unfolding intermediate which rapidly aggregates into amyloid-like fibers under physiological conditions. In this study, we examined the effects of protein concentration, pH and metals ions on the aggregation process of recombinant SEPT4-G using a series of biophysical techniques, which were also employed to study chemical unfolding and stability. Divalent metal ions caused significant acceleration to the rate of SEPT4-G aggregation. Urea induced unfolding was shown to proceed via the formation of a partially unfolded intermediate state which unfolds further at higher urea concentrations. The intermediate is a compact dimer which is unable to bind GTR At 1 M urea concentration, the intermediate state was plagued by irreversible aggregation at temperatures above 30 degrees C. However, higher urea concentration resulted in a marked decay of the aggregation, indicating that the partially folded structures may be necessary for the formation of these aggregates. The results presented here are consistent with the recently determined crystal structure of human septins and shed light on the aggregation properties of SEPT4 pertinent to its involvement in neurodegenerative disease. (C) 2008 Elsevier B.V. All rights reserved.

Synthesis Optimization of Hydroxymethylnitrofurazone, an Antichagasic Candidate, Using 3(2) Factorial Design

Hydroxymethylnitrofurazone presents in vitro activity against Trypanosoma cruzi. The optimization of the synthesis of this compound was performed through a 3(2) factorial statistical design. Quadratic model produced the best response surface predicting a maximum yield (82%) close to the center design point with a seven hours reaction and a 1:1.5 (NF:K(2)CO(3)) ratio.

Volsurf Descriptors to Analyse Anti-HCV and Cytotoxic Activities of Sesquiterpene Lactones from Asteraceae Family

Various significant anti-HCV and cytotoxic sesquiterpene lactones (SLs) have been characterized. In this work, the chemometric tool Principal Component Analysis (PCA) was applied to two sets of SLs and the variance of the biological activity was explored. The first principal component accounts for as much of the variability in the data as possible, and each succeeding component accounts for as much of the remaining variability as possible. The calculations were performed using VolSurf program. For anti-HCV activity, PC1 (First Principal Component) explained 30.3% and PC2 (Second Principal Component) explained 26.5% of matrix total variance, while for cytotoxic activity, PC1 explained 30.9% and PC2 explained 15.6% of the total variance. The formalism employed generated good exploratory and predictive results and we identified some structural features, for both sets, important to the suitable biological activity and pharmacokinetic profile.

Synthesis of 4-iodopyrazoles: A Brief Review

The selective incorporation of halogen into organic molecules provides a challenge to academic and industrial research. This microreview presents an overview of the available methodologies for the synthesis of 4-iodopyrazoles, valuable precursors for the selective construction of highly functionalized organic molecules of synthetic and biological importance.

Estrogen receptor: Structural differences and potential implications on selectivity examined by the GRID/CPCA approach

Selective Estrogen Receptor Modulators ( SERMs) have been developed, but the selectivity towards the subtypes ( ER or ER is not well understood. Based on three-dimensional structural properties of ligand binding domains, a model that takes into account this aspect was developed via molecular interaction fields and consensus principal component analysis (GRID/CPCA).

Immobilized analogues of sunflower trypsin inhibitor-1 constitute a versatile group of affinity sorbents for selective isolation of serine proteases

Sunflower trypsin inhibitor-1 (SFI-1), a natural 14-residue cyclic peptide, and some of its synthetic acyclic variants are potent protease inhibitors displaying peculiar inhibitory profiles. Here we describe the synthesis and use of affinity sorbents prepared by coupling SFTI-1 analogues to agarose resin. Chymotrypsinand trypsin-like proteases could then be selectively isolated from pancreatin; similarly, other proteases were obtained from distinct biological sources. The binding capacity of [Lys5]-SFTI-1-agarose for trypsin was estimated at over 10 mg/mL of packed gel. SFTI-1-based resins could find application either to improve the performance of current purification protocols or as novel protease-discovery tools in different areas of biological investigation. (C) 2009 Elsevier B.V. All rights reserved.

Koldiffusionens inverkan på utmattnings-hållfastheten hos varmvalsade sexkantsstänger;The influence of carbon diffusion on the fatigue strength of hot rolled hexagonal rods

Helstångsborr och konstång kallas bergborrverktyg, som tillverkas av sexkantiga stänger med inre hål för ledning av spolvatten. Dessa spolhål är klädda med ferritiskt rostfritt stål. Innan valsning borras ett centrerat hål i stålämnet som ska valsas. I det borrade hålet appliceras ett rör av ferritiskt rostfritt stål och i det röret skjuts en manganstålskärna in. Efter valsning dras kärnan ut och ett spolhål med invändigt foder av rostfritt stål bildas. Under uppvärmningen och valsningen av stålämnet sker normalt en koldiffusion från manganstålskärnan till det rostfria fodret. Fodrets syfte är att skydda spolhålets yta mot erosion och korrosion.Syftet med arbetet var att hitta en metod som garanterar uppkolning av det invändiga fodret, samt att utreda vad uppkolningen betyder för den mekaniska hållfastheten i stängerna. Ett laboratorieförsök visade att det var bra, med avseende på uppkolning, att blanda stearat i kärnbestrykningsmedlet. Kärnbestrykningsmedlet penslas på manganstålskärnan innan den förs in i stålämnet som ska valsas, dess syfte är att minska friktionen vid kärnutdragningen efter valsning.Ett försök utfördes i valsverket med stearat i kärnbestrykningsmedlet. En grundlig undersökning utfördes på två hetor som valsats med stearat-bestrykningsmedel, samt på en traditionellt tillverkad heta för att ha som referens. Hetorna kapades till provstänger om 1,5 m, totalt undersöktes 55 st.Utvärderingen av verksförsöket visade att stängernas kvalitet blir tillräckligt bra om ingenting oförutsett händer i produktionen, oavsett om koltillskott är tillsatt i bestrykningsmedlet eller inte. Arbetet gav inte en garanterande metod, men visade att stängerna normalt håller hög kvalitet.

Skolan och medierna – en förälskelse med förhinder? : Mediepedagogisk diskussion med avstamp i gymnasieungdomars reception av Härskarringen

Syftet med denna uppsats är att utifrån en receptionsanalys av Härskarringens bilder av män diskutera mediepedagogikens roll i skolan, samhället och i elevens skapande av en egen kulturell identitet. Jag har genomfört två gruppintervjuer med totalt sex respondenter, tre pojkar och tre flickor. Detta källmaterial analyserades med hjälp av annan vetenskaplig forskning och teori. Min undersökning visar att elevers kulturella identitet delvis är sammankopplad med hur man uppfattar medier. Respondenterna problematiserade även medias inverkan i skapandet av en kulturell identitet. De menade att det var lätt att ryckas med i handling och de värderingar som finns i Härskarringen. Men de uttryckte också en vilja att kunna titta kritiskt på populärkulturen och hålla sig på avstånd. Uppsatsen utmynnar i en vilja om en generell mediepedagogik som genomsyras av en förståelse för elevens befintliga och pågående kulturella identitetsprocess.