Identification of Potential New Aedes aegypti Juvenile Hormone Inhibitors from N-Acyl Piperidine Derivatives: A Bioinformatics Approach

Aedes aegypti mosquitoes transmit several human pathogens that cause millions of deaths worldwide, mainly in Latin America. The indiscriminate use of insecticides has resulted in the development of species resistance to some such compounds. Piperidine, a natural alkaloid isolated from Piper nigrum, has been used as a hit compound due to its larvicidal activity against Aedes aegypti. In the present study, piperidine derivatives were studied through in silico methods: pharmacophoric evaluation (PharmaGist), pharmacophoric virtual screening (Pharmit), ADME/Tox prediction (Preadmet/Derek 10.0 (R)), docking calculations (AutoDock 4.2) and molecular dynamics (MD) simulation on GROMACS-5.1.4. MP-416 and MP-073 molecules exhibiting Delta G binding (MMPBSA -265.95 +/- 1.32 kJ/mol and -124.412 +/- 1.08 kJ/mol, respectively) and comparable to holo (Delta G binding = -216.21 +/- 0.97) and pyriproxyfen (a well-known larvicidal, Delta G binding= -435.95 +/- 2.06 kJ/mol). Considering future in vivo assays, we elaborated the theoretical synthetic route and made predictions of the synthetic accessibility (SA) (SwissADME), lipophilicity and water solubility (SwissADME) of the promising compounds identified in the present study. Our in silico results show that MP-416 and MP-073 molecules could be potent insecticides against the Aedes aegypti mosquitoes.Pro-Reitoria de Pesquisa e Pos-Graduacao (PROPESP) of Federal University of Para via the Graduate Program in Medicinal Chemistry and Molecular Modeling, Health Science Institute, Federal University of Para PROPESP/UFPA-Edital 02/2022-PAPQ/PROPES

Marruecos al natural en la obra del pintor José Cruz Herrera (1890-1972)

Se sintetiza el contenido de una exposición sobre temática marroquí del pintor José Cruz HerreraAn exhibition about Moroccan themes of José Cruz Herrera painter is carried ou

Argumentos para una exposición: José Cruz Herrera (1890-1972)

Se sintetiza el contenido de una exposición sobre temática marroquí del pintor José Cruz Herrera.An exposition about morish objectives of José Cruz Herrera pinter is carried out

Identification of Potential Insect Growth Inhibitor against Aedes aegypti: A Bioinformatics Approach

Aedes aegypti is the main vector that transmits viral diseases such as dengue, hemorrhagic dengue, urban yellow fever, zika, and chikungunya. Worldwide, many cases of dengue have been reported in recent years, showing significant growth. The best way to manage diseases transmitted by Aedes aegypti is to control the vector with insecticides, which have already been shown to be toxic to humans; moreover, insects have developed resistance. Thus, the development of new insecticides is considered an emergency. One way to achieve this goal is to apply computational methods based on ligands and target information. In this study, sixteen compounds with acceptable insecticidal activities, with 100% larvicidal activity at low concentrations (2.0 to 0.001 mg center dot L-1), were selected from the literature. These compounds were used to build up and validate pharmacophore models. Pharmacophore model 6 (AUC = 0.78; BEDROC = 0.6) was used to filter 4793 compounds from the subset of lead-like compounds from the ZINC database; 4142 compounds (dG < 0 kcal/mol) were then aligned to the active site of the juvenile hormone receptor Aedes aegypti (PDB: 5V13), 2240 compounds (LE < -0.40 kcal/mol) were prioritized for molecular docking from the construction of a chitin deacetylase model of Aedes aegypti by the homology modeling of the Bombyx mori species (PDB: 5ZNT), which aligned 1959 compounds (dG < 0 kcal/mol), and 20 compounds (LE < -0.4 kcal/mol) were predicted for pharmacokinetic and toxicological prediction in silico (Preadmet, SwissADMET, and eMolTox programs). Finally, the theoretical routes of compounds M01, M02, M03, M04, and M05 were proposed. Compounds M01-M05 were selected, showing significant differences in pharmacokinetic and toxicological parameters in relation to positive controls and interaction with catalytic residues among key protein sites reported in the literature. For this reason, the molecules investigated here are dual inhibitors of the enzymes chitin synthase and juvenile hormonal protein from insects and humans, characterizing them as potential insecticides against the Aedes aegypti mosquito.Laboratory of Cellular Immunology Applied to Health of the Oswaldo Cruz Foundation (FIOCRUZ)Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy of the University of Granada (Spain)Researcher Assistance Program-PAPESQ/UNIFA

N-Aryltetrahydroisoquinoline derivatives as HA-CD44 interaction inhibitors: design, synthesis, computational studies, and antitumor effect

Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejmech.2023.115570.Funding This research was funded by the Consejería de Universidad, Inves- tigaci´on e Innovaci´on of the Junta de Andalucía and FEDER, Una manera de hacer Europa (P18-RT-1679, PT18-TP-4160, B-FQM-475- UGR18 and PAIDI-TC-PVT-PSETC-2.0.), the Research Results Transfer Office (OTRI) of the University of Granada (PR/17/006), the Spanish Ministry of Economy and Competitiveness (PID2019.110987RB.I00 and PID2021.128109OB.I00) and the Health Institute Carlos III (DTS18/ 00121). C.D. thanks HECBioSim, the UK High End Computing Con- sortium for Biomolecular Simulation (hecbiosim.ac.uk), which is sup- ported by the EPSRC (EP/L000253/1) for awarding computing time in Jade, a UK Tier-2 resource. B.R.-R. gratefully acknowledges funding from the European Union’s Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant Agreement no. 754446 and UGR Research and Knowledge Transfer Fund—Athenea3i. J.M.E.-R. thanks the Spanish Ministry of Education for a studentship (FPU 16/ 02061). A.M.-M. gratefully acknowledges funding from the HPC- Europa3 Transnational Access programme supported by the European Commission H2020 Research & Innovation GA # 730897 (application number HPC17ARM6V). Funding for open access charge: Universidad de Granada / CBUA.Hyaluronic acid (HA) plays a crucial role in tumor growth and invasion through its interaction with cluster of differentiation 44 (CD44), a non-kinase transmembrane glycoprotein, among other hyaladherins. CD44 expression is elevated in many solid tumors, and its interaction with HA is associated with cancer and angiogenesis. Despite efforts to inhibit HA-CD44 interaction, there has been limited progress in the development of small molecule inhibitors. As a contribution to this endeavour, we designed and synthesized a series of N-aryltetrahydroisoquinoline derivatives based on existing crystallographic data available for CD44 and HA. Hit 2e was identified within these structures for its antiproliferative effect against two CD44+ cancer cell lines, and two new analogs (5 and 6) were then synthesized and evaluated as CD44-HA inhibitors by applying computational and cell-based CD44 binding studies. Compound 2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-5-ol (5) has an EC50 value of 0.59 μM against MDA-MB-231 cells and is effective to disrupt the integrity of cancer spheroids and reduce the viability of MDA-MB-231 cells in a dose-dependent manner. These results suggest lead 5 as a promising candidate for further investigation in cancer treatment.Consejería de Universidad, Investigación e Innovación of the Junta de Andalucía and FEDER, Una manera de hacer Europa (P18-RT-1679, PT18-TP-4160, B-FQM-475- UGR18 and PAIDI-TC-PVT-PSETC-2.0.)Research Results Transfer Office (OTRI) of the University of Granada (PR/17/006),panish Ministry of Economy and Competitiveness (PID2019.110987RB.I00 and PID2021.128109OB.I0)Health Institute Carlos III (DTS18/ 00121)EPSRC (EP/L000253/1)European Union’s Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant Agreement no. 754446HPC-Europa3 Transnational Access programme supported by the European Commission H2020 Research & Innovation GA # 730897Funding for open access charge: Universidad de Granada / CBUA

Selective Anticancer Therapy Based on a HA-CD44 Interaction Inhibitor Loaded on Polymeric Nanoparticles

This research was funded by the Consejeria de Economia, Conocimiento, Empresas y Universidad of the Junta de Andalucia (grant number Excellence Research Project P18-RT-1679) and the Research Results Transfer Office (OTRI) of the University of Granada (grant number PR/17/006 project). This work was partially supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO), grant number PID2019.110987RB.I00; the Health Institute Carlos III (ISCIII), grant number DTS18/00121 the Junta de Andalucia-FEDER, Ministry of Economy, Knowledge, Companies, and University (FEDER 2018: ref. B-FQM-475-UGR18, PAIDI2020: ref. PT18-TP-4160); and the Andalusian Regional Government, grant number PAIDI-TC-PVT-PSETC-2.0. C.D. thanks HECBioSim, the UK High End Computing Consortium for Biomolecular Simulation (hecbiosim.ac.uk), which is supported by the EPSRC (EP/L000253/1) for awarding computing time in Jade, a UK Tier-2 resource. B.R.-R. gratefully acknowledges funding from the European Union's Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant Agreement no. 754446 and UGR Research and Knowledge Transfer Fund-Athenea3i. J.M.E.-R. thanks the Spanish Ministry of Education for PhD funding (scholarship FPU 16/02061). V.C.-C. thanks the Andalusian Regional Government for her postdoctoral fellowship (POSTDOC_21_00118).Hyaluronic acid (HA), through its interactions with the cluster of differentiation 44 (CD44), acts as a potent modulator of the tumor microenvironment, creating a wide range of extracellular stimuli for tumor growth, angiogenesis, invasion, and metastasis. An innovative antitumor treatment strategy based on the development of a nanodevice for selective release of an inhibitor of the HACD44 interaction is presented. Computational analysis was performed to evaluate the interaction of the designed tetrahydroisoquinoline-ketone derivative (JE22) with CD44 binding site. Cell viability, efficiency, and selectivity of drug release under acidic conditions together with CD44 binding capacity, effect on cell migration, and apoptotic activity were successfully evaluated. Remarkably, the conjugation of this CD44 inhibitor to the nanodevice generated a reduction of the dosis required to achieve a significant therapeutic effect.Junta de Andalucia P18-RT-1679Research Results Transfer Office (OTRI) of the University of Granada PR/17/006Spanish Government PID2019.110987RB.I00Health Institute Carlos III (ISCIII) DTS18/00121Junta de Andalucia-FEDER, Ministry of Economy, Knowledge, Companies, and University (FEDER) B-FQM-475-UGR18 PT18-TP-4160Andalusian Regional Government POSTDOC_21_00118UK Research & Innovation (UKRI)Engineering & Physical Sciences Research Council (EPSRC) EP/L000253/1European Union's Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant 754446UGR Research and Knowledge Transfer Fund-Athenea3iSpanish Government FPU 16/0206

An effective polymeric nanocarrier that allows for active targeting and selective drug delivery in cell coculture systems

In this manuscript, we report the development of a versatile, robust, and stable targeting nanocarrier for active delivery. This nanocarrier is based on bifunctionalized polymeric nanoparticles conjugated to a monoclonal antibody that allows for active targeting of either (i) a fluorophore for tracking or (ii) a drug for monitoring specific cell responses. This nanodevice can efficiently discriminate between cells in coculture based on the expression levels of cell surface receptors. As a proof of concept, we have demonstrated efficient delivery using a broadly established cell surface receptor as the target, the epidermal growth factor receptor (EGFR), which is overexpressed in several types of cancers. Additionally, a second validation of this nanodevice was successfully carried out using another cell surface receptor as the target, the cluster of differentiation 147 (CD147). Our results suggest that this versatile nanocarrier can be expanded to other cell receptors and bioactive cargoes, offering remarkable discrimination efficiency between cells with different expression levels of a specific marker. This work supports the ability of nanoplatforms to boost and improve the progress towards personalized medicine.Health Institute Carlos III (ISCIII) DTS18/00121Junta de Andalucia-FEDER, Ministry of Economy, Knowledge, Companies and University (University of Granada) B-FQM-475-UGR18 PT18-TP-1490 AT17_6096- OTRISpanish State Research Agency RED2018-102469-TFundación Benéfica Anticáncer San Francisco Javier y Santa CándidaSpanish Ministry of Economy and Competitiveness PTQ-16- 08597Spanish Government FPU 16/0206

Identification of Potential COX-2 Inhibitors for the Treatment of Inflammatory Diseases Using Molecular Modeling Approaches

Conceptualization, P.H.F.A., W.J.C.M. and C.B.R.S.; methodology, P.H.F.A. and C.B.R.S..; software, R.S.R. and E.F.B.F.; validation, P.H.F.A., S.G.S., L.R.d.L., J.M.E.-R. and C.B.R.S,; formal analysis, P.H.F.A., R.S.R., J.N.d.C., J.M.C. and C.B.R.S.; investigation, P.H.F.A., R.S.R. and C.B.R.S..; resources, P.H.F.A., W.J.C.M., R.S.R. and C.B.R.S.; data curation, P.H.F.A., R.S.R. and C.B.R.S.; writing—original draft preparation, P.H.F.A. and C.B.R.S.; writing—review and editing, J.M.C and J.N.d.C.; visualization, P.H.F.A.; supervision, C.B.R.S.; project administration, C.B.R.S.; funding acquisition, J.M.C., C.B.R.S., P.H.F.A.,W.J.C.M and E.F.B.F. All authors have read and agreed to the published version of the manuscript.Non-steroidal anti-inflammatory drugs are inhibitors of cyclooxygenase-2 (COX-2) that were developed in order to avoid the side e ects of non-selective inhibitors of COX-1. Thus, the present study aims to identify new selective chemical entities for the COX-2 enzyme via molecular modeling approaches. The best pharmacophore model was used to identify compounds within the ZINC database. The molecular properties were determined and selected with Pearson’s correlation for the construction of quantitative structure–activity relationship (QSAR) models to predict the biological activities of the compounds obtained with virtual screening. The pharmacokinetic/toxicological profiles of the compounds were determined, as well as the binding modes through molecular docking compared to commercial compounds (rofecoxib and celecoxib). The QSAR analysis showed a fit with R = 0.9617, R2 = 0.9250, standard error of estimate (SEE) = 0.2238, and F = 46.2739, with the tetra-parametric regression model. After the analysis, only three promising inhibitors were selected, Z-964, Z-627, and Z-814, with their predicted pIC50 (-log IC50) values, Z-814 = 7.9484, Z-627 = 9.3458, and Z-964 = 9.5272. All candidates inhibitors complied with Lipinski’s rule of five, which predicts a good oral availability and can be used in in vitro and in vivo tests in the zebrafish model in order to confirm the obtained in silico data.CAPESUNIFAP/UEA

Galantamine Based Novel Acetylcholinesterase Enzyme Inhibitors: A Molecular Modeling Design Approach

Acetylcholinesterase (AChE) enzymes play an essential role in the development ofAlzheimer’s disease (AD). Its excessive activity causes several neuronal problems, particularly psychopathies and neuronal cell death. A bioactive pose on the hAChE B site of the human acetylcholinesterase (hAChE) enzyme employed in this investigation, which was obtained from the Protein Data Bank (PDB ID 4EY6), allowed for the prediction of the binding affinity and free binding energy between the protein and the ligand. Virtual screening was performed to obtain structures similar to Galantamine (GNT) with potential hAChE activity. The top 200 hit compounds were prioritized through the use of filters in ZincPharmer, with special features related to the pharmacophore. Critical analyses were carried out, such as hierarchical clustering analysis (HCA), ADME/Tox predictions, molecular docking, molecular simulation studies, synthetic accessibility (SA), lipophilicity, water solubility, and hot spots to confirm the stable binding of the two promising molecules (ZINC16951574-LMQC2, and ZINC08342556-LMQC5). The metabolism prediction, with metabolites M3-2, which is formed by Glutathionation reaction (Phase II), M1-2, and M2-2 formed from the reaction of S-oxidation and Aliphatic hydroxylation (Phase I), were both reactive but with no side effects. Theoretical synthetic routes and prediction of synthetic accessibility for the most promising compounds are also proposed. In conclusion, this study shows that in silico modeling can be used to create new drug candidate inhibitors for hAChE. The compounds ZINC16951574-LMQC2, and ZINC08342556-LMQC5 are particularly promising for oral administration because they have a favorable drug-likeness profile, excellent lipid solubility, high bioavailability, and adequate pharmacokinetics.PROPESP/UFP

Drought as a possible contributor to the Visigothic Kingdom crisis and Islamic expansion in the Iberian Peninsula

Abstract The Muslim expansion in the Mediterranean basin was one the most relevant and rapid cultural changes in human history. This expansion reached the Iberian Peninsula with the replacement of the Visigothic Kingdom by the Muslim Umayyad Caliphate and the Muslim Emirate of Córdoba during the 8th century CE. In this study we made a compilation of western Mediterranean pollen records to gain insight about past climate conditions when this expansion took place. The pollen stack results, together with other paleohydrological records, archaeological data and historical sources, indicate that the statistically significant strongest droughts between the mid-5th and mid-10th centuries CE (450–950 CE) occurred at 545–570, 695–725, 755–770 and 900–935 CE, which could have contributed to the instability of the Visigothic and Muslim reigns in the Iberian Peninsula. Our study supports the great sensitivity of the agriculture-based economy and socio-political unrest of Early Medieval kingdoms to climatic variations