1,720,994 research outputs found
Use of MIF-based VolSurf Descriptors in Physicochemical and Pharmacokinetic Studies
No full textThe abstract is not availabl
The flavonoid scaffold as a template for the design of modulators of the vascular Cav1.2 channels
No full textBACKGROUND AND PURPOSE: Previous studies have pointed to the plant flavonoids myricetin and quercetin as two structurally related stimulators of vascular Ca(v) 1.2 channel current (I(Ca1.2) ). Here we have tested the proposition that the flavonoid structure confers the ability to modulate Ca(v) 1.2 channels.
EXPERIMENTAL APPROACH: Twenty-four flavonoids were analysed for their effects on I(Ca1.2) in rat tail artery myocytes, using the whole-cell patch-clamp method.
KEY RESULTS: Most of the flavonoids stimulated or inhibited I(Ca1.2) in a concentration- and voltage-dependent manner with EC(50) values ranging between 4.4 μM (kaempferol) and 16.0 μM (myricetin) for the stimulators and IC(50) values between 13.4 μM (galangin) and 100 μM [(±)-naringenin] for the inhibitors. Key structural requirements for I(Ca1.2) stimulatory activity were the double bond between C2 and C3 and the hydroxylation pattern on the flavonoid scaffold, the latter also determining the molecular charge, as shown by molecular modelling techniques. Absence of OH groups in the B ring was key in I(Ca1.2) inhibition. The functional interaction between quercetin and either the stimulator myricetin or the antagonists resokaempferol, crysin, genistein, and 5,7,2'-trihydroxyflavone revealed that quercetin expressed the highest apparent affinity, in the low μM range, for Ca(v) 1.2 channels. Neither protein tyrosine kinase nor protein kinase Cα were involved in quercetin-induced stimulation of I(Ca1.2).
CONCLUSIONS AND IMPLICATIONS: Quercetin-like plant flavonoids were active on vascular Ca(v)1.2 channels. Thus, the flavonoid scaffold may be a template for the design of novel modulators of vascular smooth muscle Ca(v)1.2 channels, valuable for the treatment of hypertension and stroke
The Complexity of Molecular Interaction: Molecular Shape Fingerprints by the PathFinder Approach
No full textThe abstract is not availabl
Integrating Crystallography into Early Metabolism Studies
No full textSince bioavailability, activity, toxicity, distribution, and final elimination all depend on metabolic biotransformations, it would be extremely advantageous if this information to be produced early in the discovery phase. Once obtained, researchers can judge whether or not a potential candidate should be eliminated from the pipeline, or modified to improve chemical stability or safety. The use of in silico methods to predict the site of metabolism in Phase I cytochrome-mediated reactions is a starting point in any metabolic pathway prediction. This paper presents a new method, which provides the site of metabolism for any CYP-mediated reaction acting on unknown substrates. The methodology can be applied automatically to all the cytochromes whose Xray 3D structure is known, but can be also applied to homology model 3D structures. The fully automated procedure can be used to detect positions that should be protected in order to avoid metabolic degradation, or to check the suitability of a new scaffold or pro-drug. Therefore the procedure is also a valuable new tool in early ADME-Tox, where drug-safety and metabolic profile patterns must be evaluated as soon, and as early, as possible
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
Combining machine learning and quantum mechanics yields more chemically aware molecular descriptors for medicinal chemistry applications
Full text linkMolecular interaction fields (MIFs), describing molecules in terms of their ability to interact with any chemical entity, are one of the most established and versatile concepts in drug discovery. Improvement of this molecular description is highly desirable for in silico drug discovery and medicinal chemistry applications. In this work, we revised a well-established molecular mechanics' force field and applied a hybrid quantum mechanics and machine learning approach to parametrize the hydrogen-bonding (HB) potentials of small molecules, improving this aspect of the molecular description. Approximately 66,000 molecules were chosen from available drug databases and subjected to density functional theory calculations (DFT). For each atom, the molecular electrostatic potential (EP) was extracted and used to derive new HB energy contributions; this was subsequently combined with a fingerprint-based description of the structural environment via partial least squares modeling, enabling the new potentials to be used for molecules outside of the training set. We demonstrate that parameter prediction for molecules outside of the training set correlates with their DFT-derived EP, and that there is correlation of the new potentials with hydrogen-bond acidity and basicity scales. We show the newly derived MIFs vary in strength for various ring substitution in accordance with chemical intuition. Finally, we report that this derived parameter, when extended to non-HB atoms, can also be used to estimate sites of reaction
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
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