1,720,986 research outputs found
Computational studies of the resistance patterns of mutant HIV-1 aspartic proteases towards ABT-538 (ritonavir) and design of new derivatives.
No full textKinetic characterization and cross resistance pattern studies of HIV-1 aspartic protease (PR) inhibitors have shown that some mutations cause considerable reduction in inhibition efficiency. We have performed a computational study of the binding of ABT-538 (ritonavir) with wild type (wt) PR and 12 model mutant structures (R8Q, V32I, M46I, V82A, V82F, V82I, I84V, M46I/V82F, M46I/I84V, V32I/I84V, V82F/I84V and V32I/K45I/F53L/A71V/I84V/L89M (6X)) for which inhibition data are available. Our computational studies indicate a significant correlation between computed complexation energies of ABT-538 with the modeled mutant enzyme structures and the corresponding experimental inhibition constants. By evaluating non-bonding interaction energies between the inhibitor and the mutant enzymes, we have carried out a mechanistic analysis to ascertain the reasons underlying the decrease in binding affinities. This analysis indicated that several residues in addition to the mutated residues contribute to the loss of binding. Taking these considerations into account, a number of new derivatives of ABT-538 were designed, so as to increase van der Waal's and hydrogen bonding interactions with selected mutants. A significant improvement in calculated complexation energies towards both mutant and wt PR structures was obtained for several of the redesigned analogues
Rational design of inhibitors for drug-resistant HIV-1 aspartic protease mutants
No full textThis report describes a method for the assessment of inhibitor binding affinities to wild type HIV-1 aspartic protease and to its drug-resistant mutant forms. We have elaborated a refined method for molecular modeling of the 3D structures of mutant enzymes and enzyme-inhibitor complexes based on the crystal structure of the wild type form, which employs a full thermodynamic cycle. Model complexes of four HIV-1 aspartic protease mutants with ten analogs of the A77003 inhibitor were considered. Predictions of inhibition efficiency, resistance potential, and hydrophilicity of the redesigned A77003 analogs were obtained by employing molecular mechanics for the evaluation of enzyme-inhibitor complexation energy and the polarizable continuum model for the estimation of solvent effects. Simple qualitative indicators for structural modifications aimed at overcoming the emergence of HIV resistance to protease inhibitors and at increasing the bioavailability of pseudopeptide inhibitors are examined. A semi-quantitative method for the description of enzyme-ligand binding and its implications for the rational design of inhibitors with higher binding affinity towards emerging HIV PR mutants is presented
Design of new inhibitors of HIV-1 aspartic protease
No full textWe present an approach for designing new inhibitors (I) of HIV-1 aspartic protease (PR) based on calculation of relative binding energies, taking into account contributions from all species involved in the complexation equilibrium (I + PR ⇔ I:PR), as well as their solvation. This allows a rational design of new structures with predicted enhanced inhibitory potency. We have also analysed the role in binding affinity of the central non-scissile bond (X1-X2) as well as of flanking amino acid residues Pn of inhibitor structures (P3-P2-P1-X1-X2-P1′-P2′-P3′)
Flexible synthesis of symmetric and non-symmetric hiv-1 protease inhibitors based on all-s-diaminodiol isosteres
No full textC2 symmetric and non-symmetric pseudopeptide inhibitors of HIV-1 protease, containing a S,S,S,S-diaminodiol isostere have been obtained by a synthetic strategy designed to couple a high degree of stereochemical control with complete flexibility in the choice of residues in the central core and flanking chains. Using this approach, inhibitors with IC50 values in the low nanomolar range were assembled from readily available aminoacids and carboxylic acids, chosen with the aid of molecular modelling
Stereoselective Synthesis of non Symmetric Dihydroxyethylene Dipeptide Isosteres via Epoxyalcohols Derived from alpha-Amino Acids
No full textC2 symmetric and non-symmetric pseudopeptide inhibitors of HIV-1 protease, containing a S,S,S,S-diaminodiol isostere have been obtained by a synthetic strategy designed to couple a high degree of stereochemical control with complete flexibility in the choice of residues in the central core and flanking chains. Using this approach, inhibitors with IC50 values in the low nanomolar range were assembled from readily available aminoacids and carboxylic acids, chosen with the aid of molecular modelling
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
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