1,720,974 research outputs found
Pathways to exit a receptor: a dynamical view of agonists - delta-opioids interaction
No full textThe importance of delta-opioid receptors as target of a large
number of drugs is well recognized, but the molecular details
of interaction and action of the compounds are largely
unknown. In an effort to shade some light on this important
issue we performed an extensive computational study on the
interaction of two compounds, clozapine and desmetilclozapine,
with a delta-opioid receptor. According to experiments,
the lacking of a single methyl group in desmetilclozapine with
respect of clozapine makes the former more active than the
latter, providing a system well suited for a comparative study.
We investigated stable configurations of the two drugs inside
the receptor by simulating their escape routes by metadynamics,
an algorithm that allows the simulation of events that
are otherwise out of range for standard molecular dynamics
simulations. Our results point out that the action of the compound
is related to the spatial distribution of the affinity sites it
visits during its permanency. Desmetilclozapine has a larger
distribution of residues, which is interacting with, than clozapine.
However, large conformational changes of the receptor
were not observed in the presence of both compounds. Thus,
a more dynamical picture of ligand-receptor affinity is proposed
on the basis of the results obtained, involving the
competition among different stable states as well as the
interaction with the solvents. Such information might be useful
to provide hints and insights that can be exploited in more
structure-and-dynamics-oriented drug design
Recognition of Imipenem and Meropenem by the RND-Transporter MexB Studied by Computer Simulations
No full textBasic understanding of the means by which multidrug efflux systems can efficiently recognize and transport drugs constitutes a fundamental step toward development of new compounds able to tackle the continuous outbreak of new bacterial strains resistant to traditional antibiotics. We applied a series of computational techniques, from molecular docking to molecular dynamics simulations and free energy estimate methods, to determine the differences in the binding properties of imipenem and meropenem, two potent antibiotics of the carbapenem family, to MexB, the pump subunit of the major RND efflux system of Pseudomonas aeruginosa. We identified and characterized two affinity sites in the periplasmic domain of the transporter, sharing strong similarities with the distal and proximal binding pockets identified in AcrB, the homologue of MexB in Escherichia coli. According to our results, meropenem has a higher affinity to the distal binding pocket than imipenem while both compounds are weakly bound to the proximal pocket. This different behavior is mainly due to the hydration properties of the nonpharmacophore part of the two compounds, being that of imipenem less bulky and hydrophobic. Our data provide for the first time a rationale at molecular level for the experimental evidence indicating meropenem as a compound strongly affected by MexB contrary to imipenem, which is apparently poorly transported by the same pump
A Molecular Approach to Ligand-Receptor Interaction
No full textWe have studied a human delta-opioid receptor interacting with two agonists, Clozapine and Desmethylclozapine. Delta-opioid receptors belong to the family of G protein-coupled receptors, that transduce an intracellular biological signal upon activation via interaction with a ligand in the transmembrane domain. Although Clozapine and Desmethylclozapine only differ by a methyl group, experimental data have evidenced a more efficient action of Desmethylclozapine in the treatment of refractory schizophrenia. A molecular analysis may help to clarify issues related this difference. Molecular Dynamics simulations help to elucidate the microscopic mechanism of the interactions between the ligand and the receptor identifying features barely seen in experiments. However, as in our case, the time scale of the processes of interest is often too long to be approached by standard MD techniques. Thus, for our study we have used a recent technique, the metadynamics, that accelerates MD runs extending simulation times. Our results pointed out different routes of the drugs inside the receptor: Clozapine touches a larger number of competing minima far from the putative receptor active zone than Desmethylclozapine. This latter spends most of its time inside the receptor close to the residues of the active zone, inducing noticeable structural modifications. Additionally, the simulation of the entrance has provided evidence of a stronger interaction with the receptor of Desmethylclozapine than Clozapine, resulting in a more frequent entrance of the former. Clozapine exhibits a preferential interaction with the membrane because of its enhanced hydrophobicity. The free energy surfaces extracted from the simulations have been used for kinetic Monte Carlo simulations to obtain reliable residence times of the drugs inside the receptor. The whole results helps to understand how microscopic details can remarkably affect efficiency and activity of compounds, supporting the idea of a bottom-up strategy in the drug design
Meropenem vs. Imipenem interacting with MexB: structural and dynamical determinants of the efflux action on two substrates
No full textActive extrusion of drugs through efflux pumps constitutes
one of the main mechanisms of multidrug resistance in cells.
In recent years, large efforts have been devoted to the biochemical
and structural characterization of RND efflux
pumps in Gram-negative bacteria, in particular the AcrB/ATolC
system of E.Coli. Specific attention has been addressed
to the active part of the efflux system, constituted by the AcrB
unit. Despite the presence of several data, crucial questions
concerning its functioning are still open. The understanding
of the structure-dynamics-function relationship of MexB, the
analogous transporter in P. Aeruginosa, encounters even
more difficulties, because of the lack of structural data of the
transporter in complex with substrates. To shade some light
on the activity of MexB, we performed computational studies
on MexB interacting with two compounds, meropenem and
imipenem, the first known to be a good substrate, and the
second a modest one. Several techniques were used in the
present work, ranging from flexible docking [1] to standard
and targeted molecular dynamics (MD) simulations. Starting
from the published crystal structure [2] we identified the most
probable poses of the two compounds in both the original
experimental and in the MD-equilibrated structures. We used
information from AcrB binding pocket in order to find relevant
binding sites of the two compounds in the analogous binding
pocket of MexB.
Meropenem frequently lies with appropriate orientation in a
pocket similar to the one identified for doxorubicin in AcrB [3],
while the occurrence of imipenem poses in the same pocket
is very scarce. Additionally, when present in the pocket,
imipenem is located in a position that renders very unlikely its
extrusion toward the OprM docking domain during the simulation
of the functional peristalsis. The analysis of the
trajectories has provided a complete inventory of the
transporter and antibiotic hot spots, which is key information
in terms of screening and design of antibiotics and inhibitors.
[1] Zacharias M., Protein Sci 2003, 12, 1271-82.
[2] Sennhauser G., et al., J Mol Biol 2009, 389, 134-145.
[3] Murakami S., et al., Nature 2006, 443, 173-9
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
Effects of Point Mutations on the Activity of AcrB
No full textThe tripartite efflux pump AcrAB-TolC is responsible for the intrinsic and acquired multidrug resistance in Escherichia coli. Its active part, the homotrimeric transporter AcrB, is in charge of the selective binding of substrates and energy transduction.
The presence of several phenilalanine residues in the only binding pocket identified by X-ray has inspired an experimental work where the effects of single point Phe->Ala mutations on the MIC and on the efflux of several antibiotics have been determined [1,2]. Concerning the MICs, interestingly, the mutation F610A has been shown to significantly reduce the minimum inhibitory concentration of doxorubicin and many other substrates, although F610 does not appear to interact strongly with them or to be involved in the squeezing mechanism of the binding pocket suggested as preliminary step of the extrusion process. In this work, we assess the impact of the experimental mutations on the functionality of AcrB by means of computational techniques, using doxorubicin and minocycline as substrates. We found that for F610A the compounds slide deeply inside the binding pocket after mutation, increasing the strength of the interaction. During subsequent conformational alterations of the transporter, the substrates were either not extruded from the binding site or displaced along a direction other than the one associated with extrusion. The other mutations are not able to modify the binding affinity of the substrates, which are kept in positions similar to the ones assumed in the wild type protein. Our study indicates how subtle interactions determine the functionality of multidrug transporters, since decreased transport might not be simplistically correlated to decreased substrate binding affinity.
[1] Bohnert, J. A., et al. J. Bacteriol. 2008, 190, 8225-9.
[2] Bohnert, J. A.; Schuster, S.; Szymaniak-Vits, M.; Kern, W. V. PlosOne 2011, 6, e21196
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
Pathways to Exit a Receptor: Agonists and Delta-Oppioid Studied via Computer Simulations
No full textThe importance of delta-opioid receptors as target of a large number of drugs is well recognized, but the molecular details of interaction and action of the compounds are largely unknown. In an effort to shade some light on this important issue we performed an extensive computational study on the interaction of two compounds, clozapine and desmetilclozapine, with a delta-opioid receptor. According to experiments, the lacking of a single methyl group in desmetilclozapine with respect of clozapine makes the former more active than the latter, providing a system well suited for a comparative study. We investigated the escape route of the two drugs from the receptor using molecular dynamics simulations and metadynamics. Our results point out that prolonged interactions of the compounds with specific residues of the receptor do not correlate directly with their activity, having clozapine the longest interactions if compared with desmetilclozapine but being also less active. The action of the compound is related to the spatial distribution of the affinity sites it visits during its permanency. Additionally, the role of long-resident water molecules is discussed. Such information might be useful to provide hints and insights that can be exploited in more structure-and-dynamics-oriented drug design
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
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