1,720,965 research outputs found
Optimizing QSAR models for predicting ligand binding to the drug-metabolizing cytochrome P450 isoenzyme CYP2D6.
No full textThe cytochrome P450 isozyme CYP2D6 binds a large variety of drugs, oxidizing many of them, and plays a crucial role in establishing in vivo drug levels, especially in multidrug regimens. The current study aimed to develop reliable predictive models for estimating the CYP2D6 inhibition properties of drug candidates. Quantitative structure-activity relationship (QSAR) studies utilizing 51 known CYP2D6 inhibitors were carried out. Performance achieved using models based on two-dimensional (2D) molecular descriptors was compared with performance using models entailing additional molecular descriptors that depend upon the three-dimensional (3D) structure of ligands. To properly compute the descriptors, all the 3D inhibitor structures were optimized such that induced-fit binding of the ligand to the active site was accommodated. CODESSA software was used to obtain equations for correlating the structural features of the ligands to their pharmacological effects on CYP2D6 (inhibition). The predictive power of all the QSAR models obtained was estimated by applying rigorous statistical criteria. To assess the robustness and predictability of the models, predictions were carried out on an additional set of known molecules (prediction set). The results showed that only models incorporating 3D descriptors in addition to 2D molecular descriptors possessed the requisite high predictive power for CYP2D6 inhibition
Binding free energy calculations of adenosine deaminase inhibitors
No full textThe interactions between four inhibitors and adenosine deaminase (ADA) were examined by calculating their binding
free energies after molecular dynamics simulations. A bonded model was used to represent the electrostatic potentials of the zinc
coordination site. The charge distribution of the model was derived by using a two-stage electrostatic potential fitting calculations.
The calculated binding free energies are in good agreement with the experimental data and the ranking of binding affinities is well
reproduced. Notably, our findings suggest that non-polar contributions play an important role for ADA–inhibitor interactions
QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP MODELS FOR PREDICTING BIOLOGICAL PROPERTIES, DEVELOPED BY COMBINING STRUCTURE- AND LIGAND-BASED APPROACHES: AN APPLICATION TO THE HUMAN ETHER-A-GO-GO-RELATED GENE POTASSIUM CHANNEL INHIBITION
No full textA strategy for developing accurate quantitative structure-activity relationship models enabling predictions of biological properties, when suitable knowledge concerning both ligands and biological target is available, was tested on a data set where molecules are characterized by high structural diversity. Such a strategy was applied to human ether-a-go-go-related gene K+ channel inhibition and consists of a combination of ligand- and structure-based approaches, which can be carried out whenever the three-dimensional structure of the target macromolecule is known or may be modeled with good accuracy. Molecular conformations of ligands were obtained by means of molecular docking, performed in a previously built theoretical model of the channel pore, so that descriptors depending upon the three-dimensional molecular structure were properly computed. A modification of the directed sphere-exclusion algorithm was developed and exploited to properly splitting the whole dataset into Training/Test set pairs. Molecular descriptors, computed by means of the codessa program, were used for the search of reliable quantitative structure-activity relationship models that were subsequently identified through a rigorous validation analysis. Finally, pIC50 values of a prediction set, external to the initial dataset, were predicted and the results confirmed the high predictive power of the model within a quite wide chemical space
Selection of a human butyrylcholinesterase-like antibody single-chain variable fragment resistant to AChE inhibitors from a phage library expressed in E. coli.
No full textOrganophosphates are potent poisoning agents that cause severe cholinergic toxicity. Current treatment has been reported to be unsatisfactory and novel antidotes are needed. In this study, we used a single-chain variable fragment (scFv) library to select a recombinant antibody fragment (WZ1-14.2.1) with butyrylcholinesterase-like catalytic activity by using an innovative method integrating genetic selection and the bait-and-switch strategy. Ellman assay demonstrated that WZ1-14.2.1 has Michaelis-Menten kinetics in the hydrolysis of all the three substrates used, acetylthiocholine, propionylthiocholine and butyrylthiocholine. Notably, the catalytic activity was resistant to the following acetylcholinesterase inhibitors: neostigmine, iso-OMPA, chlorpyrifos oxon, dichlorvos, and paraoxon ethyl. Otherwise, the enzymatic activity of WZ1-14.2.1 was inhibited by the selective butyrylcholinesterase inhibitor, ethopropazine, and by the Ser-blocking agent phenylmethanesuphonyl fluoride. A hypothetical 3D structure of the WZ1-14.2.1 catalytic site, compatible with functional results, is proposed on the basis of a molecular modeling analysis
Astacin gene family of metalloproteinases in planarians: Structural organization and tissue distribution
No full textPlanarian flatworms possess extraordinary regenerative capability and body plasticity, which rely on a composite population of stem cells, the neoblasts. Despite impressive advances have been recently achieved in the knowledge of neoblast biology, few is still known about factors that are released by differentiated tissues and influence the neoblast fate. Extracellular matrix (ECM) is a fundamental component of the stem cell niche and its remodeling affects stem cell fate. Here we provide the characterization of the astacin gene family of metalloproteinases in planarians, good candidate enzymes for generating dynamicity in the ECM. Ten and eighteen astacin isoforms were identified in the planarian species Schmidtea mediterranea and Dugesia japonica, respectively. Besides the already characterized Smedolloid, in Schmidtea mediterranea are present eight astacins with a minimal structure (a signal peptide, an activation domain and a Zn-binding catalytic domain), that are colocalized in large cells organized in a peculiar, not yet morphologically characterized, two-ring-shaped structure located in the middle of the body. A single astacin, characterized by a ShK toxin domain in its C-terminal region, has been found to be produced in gastrodermal cells
Identification of selective ligands for human fibrin recognition using high-throughput docking.
No full textThe ultimate aim of this study is to identify new molecules that are able to recognize polymerized fibrin, which is the main component of a thrombus. These selective ligands can be exposed on the surface of particular nanoparticles used for the targeted delivery of fibrinolytic drugs. The targeted delivery of these drugs is expected to help to keep under control the severe side effects which can occur if the drugs are administered systemically. The study focuses on the application of high-throughput docking methods used to screen a library of thousands of commercial compounds. The aim was to identify molecules that are potentially capable of interacting with the human fibrin γ(312-324) epitope. The best scoring compounds were purchased and tested through fluorimetric assays in order to estimate their affinity toward fibrin. The results show that the protocol proposed here for identifying new compounds of interest may provide a valuable contribution to the discovery of lead molecules for human fibrin recognition
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
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