1,720,977 research outputs found
Characterization of the species-dependent ketoprofen/albumin binding modes by induced CD spectroscopy and TD-DFT calculations
No full textThe stereospecificity of high-affinity biorecognition phenomena at the basis of the activity of drugs is an important topic of active research in medicinal chemistry. The binding of drugs to their targets or to carrier proteins may lead to the onset of an induced circular dichroism (ICD) signal, which can be detected experimentally. Quantum mechanical (QM) calculations based on density functional theory (DFT) and its time-dependent formulation (TD-DFT) can be used to determine the theoretical chiroptical response of all the possible conformations of drugs bound to their hosts; by comparison with the experimental ICD spectra of drug–host complexes, this approach can lead to the identification of possible binding modes in the absence of X-ray crystallography or NMR data. The present article reports the application of experimental electronic circular dichroism (ECD) spectroscopy, DFT conformational analysis and TD-DFT calculations to the investigation of the binding modes of (S)-ketoprofen to serum albumins. The peculiar species-dependent ICD spectra observed for the binding of (S)-ketoprofen to different serum albumins can be explained by the selection of different mutual arrangements of the phenyl moieties inside the binding pocket. Such structural elucidations contribute to a better understanding of the changes in the pharmacokinetic and pharmacodynamic profiles of drugs among different species
HPLC and circular dichroism studies on the hydrolysis of camptothecin and thiocamptothecin: the effect of sulphur on lactone stability
Full text link20-(S)-camptothecin (CPT) is a naturally-occurring alkaloid isolated from the Tibetan
tree Xi Shu (Camptotheca acuminata), which displays a strong inhibitory activity
towards type I topoisomerase (topo I). [1] Severe adverse effects and the limited
stability of the lactone moiety, which plays a key role in the inhibition mechanism,
limited the clinical potential of CPT as an antitumor agent and prompted the
development of new CPT analogues with reduced toxicity and improved pharmaco-
kinetics. A thiopyridone isostere of CPT, 20-(S)-thiocamptothecin (TCPT), was recently
developed for this purpose and showed an increase in inhibitory activity in H460, HT29
and IGROV-1 cell lines, [2] probably due to the greater stability of the lactone ring.
In the present study, the kinetics of the reversible hydrolysis reactions of CPT and
TCPT (Figure 1) from the closed lactone forms (a) to the open carboxylate forms (b) were
investigated by high-performance liquid chromatography (HPLC) and electronic circular
dichroism (ECD), both in the presence and absence of human serum albumin (HSA).
HPLC analysis was performed on CPT/HSA and TCPT/HSA mixtures using UV and fluorescence detection and a restricted access media (RAM) column, which allowed the direct separation of the lactone and
carboxylate forms without any additional purification steps for the exclusion of HSA. [3]
ECD analysis was performed at fixed wavelength directly on CPT/HSA and TCPT/HSA
mixtures, after characterisation of the induced ECD of the HSA/analyte complexes.
The amount of closed lactone form in buffered solutions at equilibrium (24 h) was found
to be significantly higher for TCPT than for CPT, and the same trend was observed in
the presence of equimolar and excess quantities of HSA. Moreover, the presence of
HSA caused a shift in the hydrolysis equilibrium of CPT and TCPT towards the
carboxylate form, due to its higher affinity towards HSA with respect to the lactone
form. Nevertheless, the fraction of closed lactone form resulted higher for TCPT than
for CPT under the same experimental conditions, confirming the improved stability of
the lactone moiety. The present study provides further insights into the stabilising
effects of oxygen/sulphur replacement in the CPT pyridone ring, and represents a valid
protocol for the analysis of new CPT derivatives as potential drug candidates.
[1] R.P. Verma, C. Hansch, Chem. Rev., 2009, 109 (1), 213-235.
[2] C. Samorì, A. Guerrini, G. Varchi et al., J. Med. Chem., 2008, 51 (10), 3040-3044.
[3] M. Pistolozzi, G. Varchi, A. Degli Esposti et al., ChemMedChem, 2011, 6 (9), 1706-1714
Binding modes of drug-albumin complexes investigated by induced CD spectroscopy and TD-DFT calculations
No full textAt the molecular level, the activity of drugs relies on a sequence of biorecognition phenomena, such as the binding to biological macromolecules, which define their pharmacological, toxicological and pharmacokinetic profiles. Physiologically-relevant interactions are usually very stereospecific: the occurrence of high binding affinities for specific stereochemical configurations or conformational arrangements of a drug is a very important research topic in the field of medicinal chemistry. When a drug is bound with high affinity to its target or to a carrier protein, e.g. a serum albumin, the conformational restraint due to the interaction may result in the insurgence of induced circular dichroism (ICD), which can be detected experimentally by spectroscopic analysis: nice examples are given by the ICD spectra of diazepam and ketoprofen complexed with human serum albumin (HSA). [1]
Quantum mechanical (QM) calculations based on time-dependent density functional theory (TD-DFT) can be used to investigate the theoretical ICD spectra of all the possible conformational arrangements of the ligand, and may result very helpful in the identification of possible binding modes. [2] The present communication will report the application of TD-DFT calculations to the investigation of the binding modes of ketoprofen and benzodiazepines to serum albumins: in particular, the stereospecific binding of the M conformation of benzodiazepines to HSA is confirmed, and the peculiar species-dependent ICD spectra observed for the binding of ketoprofen to different serum albumins can be explained by the selection of different mutual arrangements of the phenyl moieties in the binding pockets.
[1] M. Pistolozzi, C. Bertucci, Chirality 20, 552 (2008).
[2] S. Ionescu, I. Matei, C. Tablet, M. Hillebrand, Phys. Chem. Chem. Phys. 15, 11604 (2013)
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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