Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects

Phosphodiesterase (PDE) enzymes regulate the levels of cyclic nucleotides, cAMP, and/or cGMP, being attractive therapeutic targets. In order to modulate PDE activity in a selective way, we focused our efforts on the search of allosteric modulators. Based on the crystal structure of the PDE10A GAF-B domain, a virtual screening study allowed the discovery of new hits that were also tested experimentally, showing inhibitory activities in the micromolar range. Moreover, these new PDE10A inhibitors were able to decrease the nitrite production in LPS-stimulated cells, thus demonstrating their potential as anti-inflammatory agentsFinancial support from MINECO and FEDER founds (UE program) (project SAF2012-33600) is acknowledged. A.M.G. acknowledges pre-doctoral grants to the CSIC (JAEPre program)S

5-HT2 receptor binding, functional activity and selectivity in N-benzyltryptamines

The last fifteen years have seen the emergence and overflow into the drug scene of “superpotent” N-benzylated phenethylamines belonging to the “NBOMe” series, accompanied by numerous research articles. Although N-benzyl substitution of 5-methoxytryptamine is known to increase its affinity and potency at 5-HT2 receptors associated with psychedelic activity, N-benzylated tryptamines have been studied much less than their phenethylamine analogs. To further our knowledge of the activity of N-benzyltryptamines, we have synthesized a family of tryptamine derivatives and, for comparison, a few 5-methoxytryptamine analogs with many different substitution patterns on the benzyl moiety, and subjected them to in vitro affinity and functional activity assays vs. the human 5-HT2 receptor subtypes. In the binding (radioligand displacement) studies some of these compounds exhibited only modest selectivity for either 5-HT2A or 5-HT2C receptors suggesting that a few of them, with affinities in the 10–100 nanomolar range for 5-HT2A receptors, might presumably be psychedelic. Unexpectedly, their functional (calcium mobilization) assays reflected very different trends. All of these compounds proved to be 5-HT2C receptor full agonists while most of them showed low efficacy at the 5-HT2A subtype. Furthermore, several showed moderateto-strong preferences for activation of the 5-HT2C subtype at nanomolar concentrations. Thus, although some N-benzyltryptamines might be abuse-liable, others might represent new leads for the development of therapeutics for weight loss, erectile dysfunction, drug abuse, or schizophreniaThis work was supported by FONDECYT (Chile) regular research grants 1110146 and 1150868 to BKC and CONICYT doctoral grant 21140358 to MT-SS

Nose-to-brain delivery of enveloped RNA - cell permeating peptide nanocomplexes for the treatment of neurodegenerative diseases

This document is the preprint manuscript version of a published work that appeared in final form in Biomaterials, © 2019 Elsevier Ltd. after peer review and technical editing by the publisher. To access the final edited and published work see: https://doi.org/10.1016/j.biomaterials.2019.119657Direct nose-to-brain (N-to-B) delivery enables the rapid transport of drugs to the brain, while minimizing systemic exposure. The objective of this work was to engineer a nanocarrier intended to enhance N-to-B delivery of RNA and to explore its potential utility for the treatment of neurological disorders. Our approach involved the formation of electrostatically driven nanocomplexes between a hydrophobic derivative of octaarginine (r8), chemically conjugated with lauric acid (C12), and the RNA of interest. Subsequently, these cationic nanocomplexes were enveloped (enveloped nanocomplexes, ENCPs) with different protective polymers, i.e. polyethyleneglycol - polyglutamic acid (PEG-PGA) or hyaluronic acid (HA), intended to enhance their stability and mucodiffusion across the olfactory nasal mucosa. These rationally designed ENCPs were produced in bulk format and also using a microfluidics-based technique. This technique enabled the production of a scalable nanoformulation, exhibiting; (i) a unimodal size distribution with a tunable mean size, (ii) the capacity to highly associate (100%) and protect RNA from degradation, (iii) the ability to preserve its physicochemical properties in biorelevant media and prevent the premature RNA release. Moreover, in vitro cell culture studies showed the capacity of ENCPs to interact and be efficiently taken-up by CHO cells. Finally, in vivo experiments in a mouse model of Alzheimer's disease provided evidence of a statistically significant increase of a potentially therapeutic miRNA mimic in the hippocampus area and its further effect on two mRNA targets, following its intranasal administration. Overall, these findings stress the value of the rational design of nanocarriers towards overcoming the biological barriers associated to N-to-B RNA delivery and reveal their potential value as therapeutic strategies in Alzheimer's diseaseThe work was supported by the European B-Smart Consortium, which received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 721058S

La villa romana de Salar (Granada). El programa escultórico en contexto arqueológico

This work was carried out within the framework of the Project HAR2017-89004-P, sponsored by the Ministerio de Economia y Competitividad of the Government of Spain and with ERDF Funds (Fondos FEDER), and the Project PID2019-105294GB-100/AEI/10.13039/501100011033, sponsored by the Ministerio de Ciencia e Innovacion of the Government of Spain and with ERDF Funds(Fondos FEDER); as well as the Research Groups HUM 143 and HUM 402 (Plan Andaluz de Investigacion of the Junta de Andalucia). We thank the City Council of Salar (Granada) for supporting the systematic archaeological excavation project in villa Salar, approved bythe Junta de Andalucia (Consejeria de Cultura y Patrimonio Historico) as a General Research Project.During the last decade various excavation campaigns have taken place at the Roman villa of Salar (Granada, Spain), located in the province Baetica. The excavated sector corresponds to the area surrounding a large peristyle of the pars urbana. Presiding over the open courtyard on one of the shorter sides is a triclinium, which in turn is associated with a nymphaeum. The ambulacrum on the opposite side of the peristyle was also excavated, uncovering a mosaic pavement with an interesting hunting scene, as well as other rooms that open onto it. In this work, the typological and iconographic study of the sculptural program recovered is carried out. The sculptural assemblage consists of 1) two nymph sculptures discovered in the nymphaeum associated with the triclinium; and 2) a Capitoline type Venus statue, which possibly decorated another fountain located on the southern side of the peristyle. The archaeological context and petrographic analyses add to the study of the pieces, as well as the analysis of this sculptural program related to nymphaea and garden environments.Durante la última década se han desarrollado varias campañas de excavación en la villa romana de Salar (Granada, España), situada en la provincial romana de la Bética. El sector excavado corresponde a la pars urbana, articulada en torno a un gran peristilo central. Presidiendo uno de los lados cortos del patio abierto se sitúa el triclinium, asociado con un nymphaeum. El ambulacrum en el lado opuesto del peristilo ha sido también excavado, descubriéndose un pavimento de mosaico con una interesante escena de caza, así como otras habitaciones que abren a este patio. En este trabajo se aborda el estudio tipológico e iconográfico del programa escultórico de la villa. El conjunto está integrado por: dos esculturas de ninfas, descubiertas en el nymphaeum asociado con el triclinium; y 2) una estatua de Venus, tipo Capitolina, que posiblemente decorase otra fuente, localizada en el lado sur del peristilo. El contexto arqueológico y los análisis petrográficos se integran en el estudio de las piezas, así como el análisis del programa escultórico del nymphaeum y el jardín circundante.Spanish Government HAR2017-89004-PERDF Funds (Fondos FEDER)Spanish Government PID2019-105294GB-100/AEI/10.13039/501100011033ERDF Funds(Fondos FEDER) Junta de Andalucia HUM 143 HUM 40

Fingerprint-Based Machine Learning Approach to Identify Potent and Selective 5-HT2BR Ligands

The identification of subtype-selective GPCR (G-protein coupled receptor) ligands is a challenging task. In this study, we developed a computational protocol to find compounds with 5-HT2BR versus 5-HT1BR selectivity. Our approach employs the hierarchical combination of machine learning methods, docking, and multiple scoring methods. First, we applied machine learning tools to filter a large database of druglike compounds by the new Neighbouring Substructures Fingerprint (NSFP). This two-dimensional fingerprint contains information on the connectivity of the substructural features of a compound. Preselected subsets of the database were then subjected to docking calculations. The main indicators of compounds’ selectivity were their different interactions with the secondary binding pockets of both target proteins, while binding modes within the orthosteric binding pocket were preserved. The combined methodology of ligand-based and structure-based methods was validated prospectively, resulting in the identification of hits with nanomolar affinity and ten-fold to ten thousand-fold selectivitiesÁ.A.K. and G.M.K. were supported by the National Brain Research Program (2017-1.2.1-NKP-2017-00002). K.R. is grateful for the ETIUDA scholarship of the National Science Center, Poland. J.B. and M.I.L. are grateful for the support from the Spanish Ministerio de Economía y Comptetitividad (SAF2017-85225-C3-1-R)S

Membrane-disrupting iridium(III) oligocationic organometallopeptides

NOTICE: This is the peer reviewed version of the following article: Salvadó, I, Gamba, I, Montenegro J, Martínez-Costas J, Brea JM, Loza MI, Vázquez López M, Vázquez M.E. Membrane-disrupting iridium(III) oligocationic organometallopeptides. Chem. Commun., 2016,52, 11008-11011. DOI: 10.1039/C6CC05537K. This article may be used for non-commercial purposes in accordance with RSC Terms and Conditions for self-archivingA series of oligoarginine peptide derivatives containing cyclometallated iridium(III) units display remarkable cytotoxicity, comparable to that of cisplatin. In vitro studies with unilamellar vesicles support a membrane-disrupting mechanism of actionWe are thankful for the support given by the Spanish grants SAF2013-41943-R, CTQ2015-70698-R, CTQ2013-49317-EXP,CTQ2014-59646-R, and BFU2013-43513-R, and the Xunta de Galicia GRC2013-041. Support from COST Action CM1105 and the orfeo-cinqa network (CTQ2014-51912-REDC) is kindly acknowledgedS

Perturbation theory/machine learning model of ChEMBL data for dopamine targets: docking, synthesis, and assay of new l-prolyl-l-leucyl-glycinamide peptidomimetics

[Abstract] Predicting drug–protein interactions (DPIs) for target proteins involved in dopamine pathways is a very important goal in medicinal chemistry. We can tackle this problem using Molecular Docking or Machine Learning (ML) models for one specific protein. Unfortunately, these models fail to account for large and complex big data sets of preclinical assays reported in public databases. This includes multiple conditions of assays, such as different experimental parameters, biological assays, target proteins, cell lines, organism of the target, or organism of assay. On the other hand, perturbation theory (PT) models allow us to predict the properties of a query compound or molecular system in experimental assays with multiple boundary conditions based on a previously known case of reference. In this work, we report the first PTML (PT + ML) study of a large ChEMBL data set of preclinical assays of compounds targeting dopamine pathway proteins. The best PTML model found predicts 50000 cases with accuracy of 70–91% in training and external validation series. We also compared the linear PTML model with alternative PTML models trained with multiple nonlinear methods (artificial neural network (ANN), Random Forest, Deep Learning, etc.). Some of the nonlinear methods outperform the linear model but at the cost of a notable increment of the complexity of the model. We illustrated the practical use of the new model with a proof-of-concept theoretical–experimental study. We reported for the first time the organic synthesis, chemical characterization, and pharmacological assay of a new series of l-prolyl-l-leucyl-glycinamide (PLG) peptidomimetic compounds. In addition, we performed a molecular docking study for some of these compounds with the software Vina AutoDock. The work ends with a PTML model predictive study of the outcomes of the new compounds in a large number of assays. Therefore, this study offers a new computational methodology for predicting the outcome for any compound in new assays. This PTML method focuses on the prediction with a simple linear model of multiple pharmacological parameters (IC50, EC50, Ki, etc.) for compounds in assays involving different cell lines used, organisms of the protein target, or organism of assay for proteins in the dopamine pathway.Ministerio de Economía y Competitividad; CTQ2016-74881-PGobierno Vasco; IT1045-16Xunta de Galicia; GPC2014/003Xunta de Galicia; CN 2012/069Xunta de Galicia; ED431D 2017/16Xunta de Galicia; ED431D 2017/23Xunta de Galicia; GRC2014/049Xunta de Galicia; ED431D 2017/2

Análisis arqueométrico de tres esculturas romanas de la villa de Salar (Granada, España)

This paper shows the archaeometric study carried out on three Roman sculptures located in the Roman villa of Salar (Granada, Spain). These are two Nymphe sculptures and a Venus made of white marble. The different samples have been studied from a petrographic, mineralogical and geochemical point of view and have been compared with local marbles such as Almaden de la Plata, and foreign ones such as Pentelic, Paros and Naxos, in order to identify their origin. The data indicate that in the elaboration of two statues (one Nymphe and Venus) Pentelic marble has been used, and in the second sculpture of Nymphe is used a local marble, perhaps, from Almaden de la Plata This study is of interest since there are few archaeometric studies conducted on archaeological pieces in this area of Roman Baetica and consequently little is known about the areas of supply and commercial circuit of marbles in the Eastern sector of the South of Hispania.info:eu-repo/grantAgreement/MINECO/ Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/HAR2013-42078-P/[ES]/[Marmora. Innovaciones en el Estudio Arqueológico y Arqueométrico del Uso de los Marmora en la Baetica: Arquitectura, Escultura, Epigrafía

Pharmacological tools based on imidazole scaffold proved the utility of PDE10A inhibitors for Parkinson’s disease

[Aim]: Since neuroinflammation is partially mediated by cAMP levels and PDE10A enzyme is able to regulate these levels being highly expressed in striatum, its inhibitors emerged as useful drugs to mitigate this inflammatory process and hence the neuronal death associated with Parkinson’s disease (PD).[Methodology & results]: To study the utility of PDE10A as a pharmacological target for PD, in this work we propose the search and development of new PDE10A inhibitors that could be useful as pharmacological tools in models of the disease and presumably as potential drug candidates. By using different medicinal chemistry approaches we have discovered imidazole-like PDE10A inhibitors and showed their neuroprotective actions.[Conclusion]: Here, we demonstrate the neuroprotective effect of PDE10A inhibitors in cellular models of PD.Peer reviewe

8-Amide and 8-carbamate substitution patterns as modulators of 7-hydroxy-4-methylcoumarin's antidepressant profile: Synthesis, biological evaluation and docking studies

Psychiatric and neurological disorders affect millions of people worldwide. Currently available treatments may help to improve symptoms, but they cannot cure the diseases. Therefore, there is an urgent need for potent and safe therapeutic solutions. 8-Amide and 8-carbamatecoumarins were synthetized and evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Comparison between both scaffolds has been established, and we hypothesized that the introduction of different substituents can modulate hMAO activity and selectivity. N-(7-Hydroxy-4-methylcoumarin-8-yl)-4-methylbenzamide (9) and ethyl N-(7-hydroxy-4-methylcoumarin-8-yl)carbamate (20) proved to be the most active and selective hMAO-A inhibitors (IC50 = 15.0 nM and IC50 = 22.0 nM, respectively), being compound 9 an irreversible hMAO-A inhibitor twenty-four times more active in vitro than moclobemide, a drug used in the treatment of depression and anxiety. Based on PAMPA assay results, both compounds proved to be good candidates to cross the blood-brain barrier. In addition, these compounds showed non-significant cytotoxicity on neuronal viability assays. Also, the best compound proved to have a t1/2 of 6.84 min, an intrinsic clearance of 195.63 μL min−1 mg−1 protein, and to be chemically stable at pH 3.0, 7.4 and 10.0. Docking studies were performed to better understand the binding affinities and selectivity profiles for both hMAO isoforms. Finally, theoretical drug-like properties calculations corroborate the potential of both scaffolds on the search for new therapeutic solutions for psychiatric disorders as depressionThis research was funded by Consellería de Cultura, Educación e Ordenación Universitaria (EM2014/016), Ministerio de Ciencia e Innovación (PID2020-116076RJ-I00/AEI/10.13039/501100011033) and Fundação para a Ciência e Tecnologia (PTDC/ASP-PES/28397/2017, CEECIND/02423/2018, UIDB/00081/2020, LA/P/0056/2020 and EXPL/BIA-BQM/0492/2021). Financial support from the Xunta de Galicia (Centro de investigación de Galicia accreditation 2019–2022) and the European Union (European Regional Development Fund - ERDF), is also gratefully acknowledged. M.I.R.-F. acknowledges the economic support from the Spanish Ministry of Science, Innovation and Universities; Spanish Research Agency; and European Regional Development Funds (grant PID2021-122650OB-I00) and from CSIC (PIE-202080E118)S