1,720,985 research outputs found
Screening the medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18
Full text linkMalaria is a parasitic disease that remains a global health burden. The ability of the parasite to rapidly develop resistance to therapeutics drives an urgent need for the delivery of new drugs. The Medicines for Malaria Venture have compounds known for their antimalarial ac- tivity, but not necessarily the molecular targets. In this study, we assess the ability of the “MMV 400” compounds to inhibit the activity of three metalloaminopeptidases from Plasmo- dium falciparum, PfA-M1, PfA-M17 and PfM18 AAP. We have developed a multiplex assay system to allow rapid primary screening of compounds against all three metalloaminopepti- dases, followed by detailed analysis of promising compounds. Our results show that there were no PfM18AAP inhibitors, whereas two moderate inhibitors of the neutral aminopepti- dases PfA-M1 and PfA-M17 were identified. Further investigation through structure-activity relationship studies and molecular docking suggest that these compounds are competitive inhibitors with novel binding mechanisms, acting through either non-classical zinc coordina- tion or independently of zinc binding altogether. Although it is unlikely that inhibition of PfA- M1 and/or PfA-M17 is the primary mechanism responsible for the antiplasmodial activity re- ported for these compounds, their detailed characterization, as presented in this work, pave the way for their further optimization as a novel class of dual PfA-M1/PfA-M17 inhibitors uti- lising non-classical zinc binding groups
The composite influence of the imidazolone moiety of CGP 12177 on its affinity and efficacy at the two conformations of the human β1-adrenoceptor
No full textThe effect of the N-alkyl moiety on the interaction of pindolol analogues with the two agonist conformations of the human β1-adrenoceptor
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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
Structure activity relationships of novel and selective beta1-adrenoreceptor ligands
No full textOf the numerous l3-blockers clinically available to treat conditions such as angina pectoris, hypertension and heart failure, none possess antagonist activity specific to the beta1-adrenoceptor. Those described as 'cardioselective', such as nebivolol and bisoprolol, generally show less than 50-fold beta1/beta2-selectivity, which can be lost at higher doses. Others, such as propranolol and sotalol are actually more beta2-selective. Overall, a degree of concomitant beta2-adrenoceptor blockade (risking compromised respiratory function and loss of peripheral vasodilatation) by current therapeutic agents precludes their use in patients with disorders such as asthma and peripheral vascular disease.
This project aims to develop novel molecules with much improved beta1/beta2-selectivity over current beta1-blocker therapy as well as improving knowledge of ligand-receptor interaction at the beta1-adrenoceptor, through an analogue-based drug discovery approach. A highly selective or specific beta1-adrenoceptor antagonist is likely to cause fewer side-effects and be suitable for use in previously contraindicated disease states.
This thesis reports the design, synthesis and pharmacological data (provided by Dr. Jillian Baker) of a library of novel ligands for the beta1- adrenoceptor, based upon the lead compound LK 204-545. LK 204-545 was selected based on reported high potency at the beta1-adrenoceptor as well as good beta1/beta2-selectivity.
Modification of various motifs on structures derived from LK 204-545 allowed the generation of new structure-activity relationships and ultimately afforded the highly 131-adrenoceptor selective compound, 1-(2-(3-(4-(2-(cyclopropylmethoxy)ethoxy)phenoxy)-2-hydroxypropyl amino)ethyl)-3-(4-hydroxyphenyl)urea hydroformate (12Sc). This compound acted as a highly-selective beta1-adrenoceptor antagonist in a pilot in-vivo study in the regional hemodynamic rat model (carried out by
Prof. Sheila Gardiner)
Structure activity relationships of novel and selective beta1-adrenoreceptor ligands
Full text linkOf the numerous l3-blockers clinically available to treat conditions such as angina pectoris, hypertension and heart failure, none possess antagonist activity specific to the beta1-adrenoceptor. Those described as 'cardioselective', such as nebivolol and bisoprolol, generally show less than 50-fold beta1/beta2-selectivity, which can be lost at higher doses. Others, such as propranolol and sotalol are actually more beta2-selective. Overall, a degree of concomitant beta2-adrenoceptor blockade (risking compromised respiratory function and loss of peripheral vasodilatation) by current therapeutic agents precludes their use in patients with disorders such as asthma and peripheral vascular disease.
This project aims to develop novel molecules with much improved beta1/beta2-selectivity over current beta1-blocker therapy as well as improving knowledge of ligand-receptor interaction at the beta1-adrenoceptor, through an analogue-based drug discovery approach. A highly selective or specific beta1-adrenoceptor antagonist is likely to cause fewer side-effects and be suitable for use in previously contraindicated disease states.
This thesis reports the design, synthesis and pharmacological data (provided by Dr. Jillian Baker) of a library of novel ligands for the beta1- adrenoceptor, based upon the lead compound LK 204-545. LK 204-545 was selected based on reported high potency at the beta1-adrenoceptor as well as good beta1/beta2-selectivity.
Modification of various motifs on structures derived from LK 204-545 allowed the generation of new structure-activity relationships and ultimately afforded the highly 131-adrenoceptor selective compound, 1-(2-(3-(4-(2-(cyclopropylmethoxy)ethoxy)phenoxy)-2-hydroxypropyl amino)ethyl)-3-(4-hydroxyphenyl)urea hydroformate (12Sc). This compound acted as a highly-selective beta1-adrenoceptor antagonist in a pilot in-vivo study in the regional hemodynamic rat model (carried out by
Prof. Sheila Gardiner)
Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions
Full text linkMalaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. P. falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics
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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