1,720,965 research outputs found
Analysis of the molecular interactions of the potent analgesic S1RA with the σ1 receptor
No full textThe highly selective σ1 receptor antagonist S1RA is endowed with a surprisingly high affinity for its target protein given a missing fundamental hydrophobic pharmacophoric requirement. Here we show that, with respect to other potent σ1 ligands, S1RA is able to compensate this loss by fulfilling all other pharmacophoric requirements and by gaining in solvation energy
The Sigma Enigma:In Vitro/in SilicoSite-Directed Mutagenesis Studies Unveil σ1Receptor Ligand Binding
No full textThe σ1 receptor is an integral membrane protein that shares no homology with other receptor systems, has no unequivocally identified natural ligands, but appears to play critical roles in a wide variety of cell functions. While the number of reports of the possible functions of the σ1 receptor is increasing, almost no information about the three-dimensional structure of the receptor and/or possible modes of interaction of the σ1 protein with its ligands have been described. Here we performed an in vitro/in silico investigation to analyze the molecular interactions of the σ1 receptor with its prototypical agonist (+)-pentazocine. Accordingly, 23 mutant σ1 isoforms were generated, and their interactions with (+)-pentazocine were determined experimentally. All direct and/or indirect effects exerted by the mutant residues on the receptor-agonist interactions were reproduced and rationalized in silico, thus shining new light on the three-dimensional structure of the σ1 receptor and its ligand binding site
Synthesis, pharmacological evaluation and σ1 receptor interaction analysis of hydroxyethyl substituted piperazines
No full textStarting from (S)- or (R)-aspartate, three synthetic strategies were explored to prepare hydroxyethyl substituted piperazines with different substituents at the N-atoms. σ receptor affinity was recorded using receptor material from both animal and human origin. σ1 affinities determined with guinea pig brain and human RPMI 8226 tumor cell lines differed slightly but showed the same tendency. (S)-2-[4-(Cyclohexylmethyl)-1-(naphthalene-2-ylmethyl)piperazin-2-yl]ethanol (7c) revealed the highest affinity at human σ1 receptors (Ki = 6.8 nM). The potent σ1 receptor ligand 7c was able to inhibit selectively the growth of three human tumor cell lines with IC50 values in the low micromolar range. The reduced growth of the RPMI-8226 cell line was caused by apoptosis. The interaction of 7c with the σ1 receptor was analyzed in detail using the 3D homology model of the σ1 receptor. The calculated free binding energies of all hydroxyethylpiperazines nicely correlate with their recorded affinities toward the human σ1 receptor
Pd-Catalyzed Direct C-H Bond Functionalization of Spirocyclic σ(1) Ligands: Generation of a Pharmacophore Model and Analysis of the Reverse Binding Mode by Docking into a 3D Homology Model of the σ(1) Receptor.
No full textTo explore the hydrophobic binding region of the σ(1) receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective α- and β-arylation using the catalyst systems PdCl(2)/bipy/Ag(2)CO(3) and PdCl(2)/P[OCH(CF(3))(2)](3)/Ag(2)CO(3) allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing σ(1) affinity in the order 4 < 5/6 < 7/8 indicates that the positions of the additional aryl moiety and the S atom in the spirocyclic thiophene systems control the σ(1) affinity. The main features of the pharmacophore model developed for this class of σ(1) ligands are a positive ionizable group, a H-bond acceptor group, two hydrophobic moieties, and one hydrophobic aromatic group. Docking of the ligands into a σ(1) 3D homology model via molecular mechanics/Poisson-Boltzmann surface area calculations led to a very good correlation between the experimentally determined and estimated free energy of receptor binding. These calculations support the hypothesis of a reverse binding mode of ligands bearing the aryl moiety at the "top" (compounds 2, 3, 7, and 8) and "left" (compounds 4, 5, and 6) positions, respectively
Genes within Bottles. Synergism Between Simulation and Experiment in Designing Nanovectors for DNA/RNA Delivery
Get PDFDue to their relative easy synthesis and commercial availability, nanovectors based on dendrimers and dendrons are among the most utilized non-viral vectors for gene transfer. Concomitantly, recent advances in molecular simulations and computer architectures
not only allow for accurate predictions of many structural, energetical, and eventual self-assembly features of these nanocarriers per se, but are able to yield fundamental information about the interactions of these nanovectors with their nucleic acid cargoes at a molecular level. In this work, we aim at reviewing some of our own efforts in the field of multiscale molecular modeling of these fascinating materials. This review is written by computational scientists for experimental scientists, with the specific purpose of illustrating the potentiality of these methodologies and the usefulness of multiscale molecular modeling as an innovative and complementary tool in their current research
Homology Model and Docking-Based Virtual Screening for Ligands of the σ1 Receptor
No full textThis study presents for the first time the 3D model of the σ1 receptor protein as
obtained from homology modeling techniques, shows the applicability of this structure to
docking-based virtual screening, defines a computational strategy to optimize the results based on
a combination of 3D pharmacophore-based docking and MM/PBSA free energy of binding
scoring, and provides evidence that these in silico models and recipes are powerful tools on which
virtual screening of new σ1 ligands can be based. In particular, the validation of the applicability of
docking-based virtual screening to homology models is of utmost importance, since no crystal
structure is available to date for the σ1 receptor, and this missing information still constitutes a
major hurdle for a rational ligand design for this important protein target
In silico prediction of drug resistance: from cancer targeted therapy to cancer targeted prevention
Get PDF2012/2013Le recenti scoperte sulla natura dei processi genetici, implicati nelle trasformazioni neoplastiche, ci hanno permesso di identificare le principali lesioni cellulari che portano alla formazione del tumore, individuando in questo modo target selettivi sulla base dei quali progettare nuovi agenti terapeutici efficaci.
La terapia bersaglio ha rappresentato una rivoluzione permettendo di superare l’aspecificità del trattamento antitumorale e colpendo, nello specifico, la causa biomolecolare del processo patologico neoplastico.
I recenti sviluppi della modellistica molecolare si sono resi indispensabili per la ricerca oncologica.
Questi, infatti, aprono delle opportunità per la scoperta di nuovi farmaci attraverso la comprensione delle basi molecolari delle malattie; si tratta di un metodo conveniente per identificare dei composti che siano in grado di bloccare l’azione di molte proteine, suggerite come fattori fondamentali in diversi tipi di neoplasie.
In questo lavoro di tesi verrà adoperata un’ampia gamma di tecniche di simulazione molecolare al fine di studiare differenti problemi che possono comparire durante il trattamento chemioterapico. La scoperta di nuovi dettagli nei meccanismi che conducono alla carcinogenesi ha permesso di identificare proteine target innovative e più precise per affrontare la terapia senza effetti collaterali per le cellule sane. In particolare, saranno riportati in dettaglio gli studi che coinvolgono tre nuovi differenti target: il recettore σ1, la proteina -catenina e lo sviluppo di dendrimeri per una terapia di silenziamento genico.
Tuttavia, nonostante i successi clinici della terapia bersaglio, molti pazienti che inizialmente hanno risposto positivamente manifestano una recidiva, come risultato di una resistenza acquisita; questo tipo di risposta può manifestarsi dopo un periodo variabile di trattamento cronico.
L’approccio delle tecniche in silico può essere utilizzato per predire l’avvento di mutazioni secondarie attivanti e al contempo resistenti alla terapia e quindi aiutare nello sviluppo di una strategia di prevenzione focalizzata su una terapia multi-farmaco. In questo lavoro, verranno discusse in particolare delle mutazioni che coinvolgono i recettori c-Kit e Smoothened, pre e post trattamento.
L’ampia serie di esempi illustrati e discussi qui enfatizza il ruolo e le potenzialità del modeling molecolare nello sviluppo della terapia bersaglio anti tumorale. Una valutazione in silico permette di prendere in considerazione la specificità molecolare del problema e ridurre drasticamente i tempi e i costi richiesti per formulare nuovi farmaci e strategie di intervento.XXVI Ciclo198
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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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