48,117 research outputs found
Addressing the Target Identification and Accelerating the Repositioning of Anti-Inflammatory/Anti-Cancer Organic Compounds by Computational Approaches
No full textThe use of computational chemistry techniques has led to notable advances in the structural and pharmacological investigation of organic compounds. The combination of quantum mechanical (QM) approaches with experimental methods (e. g., NMR spectroscopy) has contributed to the configurational and conformational structural assignment of the investigated items. Once this information has been obtained, in silico tools have been employed for assessing the pharmacological features of natural and synthetic molecules, especially those lacking precise information about their interacting macromolecules. With this aim, we have developed and implemented the Inverse Virtual Screening (IVS) computational methodology for addressing the target identification task. This minireview focuses on the key technical information and on successful examples about the convenient and fast use of such computational methods in the frame of the drug repositioning and the discovery of anti-inflammatory/anti-cancer agents
Introduzione [Atti del 6° Congresso Internazionale dell'Associazione Italiana di linguistica Applicata]
No full textPresentazione del tema, dell'organizzazione del volume e dei singoli contributi
Deciphering the specific role of G(αi/o) isoforms: functional selective oxytocin ligands and somatostatin SST5 receptor mutants
No full textReceptor coupling to different G-proteins and β-arrestins has been described for a number of GPCRs (G-protein-coupled receptors), suggesting a multi-state model of receptor activation in which each receptor can assume a number of different active conformations, each capable of promoting the coupling to a specific effector. Consistently, functional-selective ligands and biased agonists have been described to be able to induce and/or stabilize only a subset of specific active conformations. Furthermore, GPCR mutants deficient in selective coupling have been reported. Functional selective ligands and receptor mutants thus constitute unique tools to dissect the specific roles of different effectors, in particular among the Gi/o family. In the present mini-review, we focus on (i) the identification of functional selective OXT (oxytocin)-derived peptides capable of activating single Gi/o isoforms, namely Gi1 or Gi3; and (ii) the characterization of an SS (somatostatin) receptor SST5 mutant selectively impaired in its G oA coupling. These analogues and receptor mutants represent unique tools for examining the contribution of Gi/o isoforms in complex biological responses and open the way for the development of drugs with peculiar selectivity profiles
Insights into the ligand binding to bromodomain‐containing protein 9 (BRD9): A guide to the selection of potential binders by computational methods
No full textThe estimation of the binding of a set of molecules against BRD9 protein was carried out through an in silico molecular dynamics‐driven exhaustive analysis to guide the identification of potential novel ligands. Starting from eight crystal structures of this protein co‐complexed with known binders and one apo form, we conducted an exhaustive molecular docking/molecular dynamics (MD) investigation. To balance accuracy and an affordable calculation time, the systems were simulated for 100 ns in explicit solvent. Moreover, one complex was simulated for 1 μs to assess the influence of simulation time on the results. A set of MD‐derived parameters was com-puted and compared with molecular docking‐derived and experimental data. MM‐GBSA and the per‐residue interaction energy emerged as the main indicators for the good interaction between the specific binder and the protein counterpart. To assess the performance of the proposed analysis workflow, we tested six molecules featuring different binding affinities for BRD9, obtaining prom-ising outcomes. Further insights were reported to highlight the influence of the starting structure on the molecular dynamics simulations evolution. The data confirmed that a ranking of BRD9 binders using key parameters arising from molecular dynamics is advisable to discard poor ligands be-fore moving on with the synthesis and the biological tests
Accelerating the repurposing of FDA-approved drugs against coronavirus disease-19 (COVID-19)
No full textThe recent release of the main protein structures belonging to SARS CoV-2, responsible for the coronavirus disease-19 (COVID-19), strongly pushed for identifying valuable drug treatments. With this aim, we show a repurposing study on FDA-approved drugs applying a new computational protocol and introducing a novel parameter called IVSratio. Starting with a virtual screening against three SARS CoV-2 targets (main protease, papain-like protease, spike protein), the top-ranked molecules were reassessed combining the Inverse Virtual Screening novel approach and MM-GBSA calculations. Applying this protocol, a list of drugs was identified against the three investigated targets. Also, the top-ranked selected compounds on each target (rutin vs. main protease, velpatasvir vs. papain-like protease, lomitapide vs. spike protein) were further tested with molecular dynamics simulations to confirm the promising binding modes, obtaining encouraging results such as high stability of the complex during the simulation and a good protein-ligand interaction network involving some important residues of each target. Moreover, the recent outcomes highlighting the inhibitory activity of quercetin, a natural compound strictly related to rutin, on the SARS-CoV-2 main protease, strengthened the applicability of the proposed workflow. This journal i
Controllo delle malerbe nel frutteto: risultati di prove sperimentali con prodotti alternativi/complementari al glifosate
No full textNuovi spunti sull’acquisizione del genere, tra forma e funzione
No full textRiflessioni sull'apprendimento del genere, in particolare in L1 e L2, con discussione sui fattori pertinenti, condotta in un'ottica latamente funzionalist
Heterotrimeric G proteins demonstrate differential sensitivity to beta-arrestin dependent desensitization
No full textG15 is a heterotrimeric G protein of the Gq/11 family. In this study, we describe its exceptional poor sensitivity to the general regulatory mechanism of G protein-coupled receptor (GPCR) desensitization. Enhancing beta2 adrenergic receptor desensitization by arrestin overexpression, did not affect signalling to G15. Similarly, increased levels of arrestin did not affect G15 signalling triggered by the activation of V2 vasopressin and delta opioid receptors. Furthermore, co-immunoprecipitation experiments showed that G15 alpha subunit (as opposed to Galphaq and Galphas) is recruited to a V2 vasopressin receptor mutant that is constitutively desensitized by beta-arrestin. Interestingly, co-expression of Galpha15 partially rescued cell surface localization and signalling capabilities of the same mutant receptor and reduced beta2 adrenergic receptor internalization. Taken together, these findings provide evidence for a novel mechanism whereby GPCR desensitization can be bypassed and G15 can support sustained signalling in cells chronically exposed to hormones or neurotransmitter
Selective and potent agonists and antagonists for investigating the role of mouse oxytocin receptors
No full textThe neuropeptides oxytocin (OT) and vasopressin (AVP) have been shown to play a central role in social behaviors; as a consequence, they have been recognized as potential drugs to treat neurodevelopmental and psychiatric disorders characterized by impaired social interactions. However, despite the basic and preclinical relevance of mouse strains carrying genetic alterations in the OT/AVP systems to basic and preclinical translational neuroscience, the pharmacological profile of mouse OT/AVP receptor subtypes has not been fully characterized. To fill in this gap, we have characterized a number of OT and AVP agonists and antagonists at three murine OT/AVP receptors expressed in the nervous system as follows: the oxytocin (mOTR) and vasopressin V1a (mV1aR) and V1b (mV1bR) subtypes. These three receptors were transiently expressed in vitro for binding and intracellular signaling assays, and then a homology model of the mOTR structure was constructed to investigate how its molecular features compare with human and rat OTR orthologs. Our data indicate that the selectivity profile of the natural ligands, OT and AVP, is conserved in humans, rats, and mice. Furthermore, we found that the synthetic peptide [Thr4Gly7]OT (TGOT) is remarkably selective for the mOTR and, like the endogenous OT ligand, activates Gq and Gi and recruits b-arrestins. Finally, we report three antagonists that exhibit remarkably high affinities and selectivities at mOTRs. These highly selective pharmacological tools will contribute to the investigation of the specific physiologic and pathologic roles of mOTR for the development of selective OT-based therapeutics
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