Novel Benzindoloazecines and Dibenzazecines: synthesis and affinities for the Dopamine receptors

Azecine sind eine neuartige Klasse von Dopaminrezeptor-Antagonisten, gekennzeichnet durch ihre nanomolare Affinitäten an den Dopaminrezeptoren und vor allem ihre Selektivität für die Rezeptoren der D1-Familie. Strukturwirkungsbeziehungen dieser Verbinungsklasse wurde umfassend erforscht. Die Strategie der vorliegenden Arbeit war die Strukturen der Leitverbindungen LE300 und LE404 so zu modifizieren, dass die erforderlichen strukturellen Merkmale weitgehend erhalten werden sollten. Das Benzindoloazecin LE300 wurde vielfältig modifiziert; z.B. durch Veränderung des Annellierungsmusters vom Ringgerüst oder Einfügen eines Substituents an verschiedenen Stellen. Außerdem wurde die phenolische Gruppe der Leitstruktur LE404 vom Dibenzazecin-Typ durch eine Methylendioxygruppe ersetzt. Das Ziel dieser Arbeit war die Strukturwirkungsbeziehungen dieser neuartigen Klasse von Dopaminrezeptor-Antagonisten weiter zu entwickeln, um Derivate mit höheren Affinitäten und besser ausgeprägten Subtypselektivität zu erreichen. Insgesamt wurden 29 Zielverbindungen synthetisiert und die Affinitäten an den verschiedenen Dopaminrezeptoren (human) durch Radioligandbindungsstudien ermittelt. Weiterhin wurde die Funktionalität der Verbindungen (Agonisten oder Antagonisten) mit Hilfe eines Calcium Assays bestimmt

Flow-duration curve integration into digital filtering algorithms for simulating climate variability based on river baseflow

A baseflow separation methodology combining the outcomes of the flow–duration curve and the digital filtering algorithms to cope with the restrictions of the traditional procedures has been assessed. Using this methodology as well as the monitored and simulated hydro-climatologic data, the baseflow annual variations due to climate change and human-induced activities were determined. The outcomes show that the long-term baseflow index at the upstream sub-basin is nearly half of that at the downstream from October to April, whereas, they are close to each other for the remaining months. Some of the groundwater reacts to precipitation and an evident rise in the groundwater contribution has been detected for the hydrological years 1998–2001 and 2006–2008. The contrary has been recorded for 1987. The water released from the reservoir in the dry periods lead to distinctions in the detected baseflow index between the pre-damming and post-damming periods of the river

Exploring aromatic cage flexibility of the histone methyllysine reader protein Spindlin1 and its impact on binding mode prediction : an in silico study

Some of the main challenges faced in drug discovery are pocket flexibility and binding mode prediction. In this work, we explored the aromatic cage flexibility of the histone methyllysine reader protein Spindlin1 and its impact on binding mode prediction by means of in silico approaches. We first investigated the Spindlin1 aromatic cage plasticity by analyzing the available crystal structures and through molecular dynamic simulations. Then we assessed the ability of rigid docking and flexible docking to rightly reproduce the binding mode of a known ligand into Spindlin1, as an example of a reader protein displaying flexibility in the binding pocket. The ability of induced fit docking was further probed to test if the right ligand binding mode could be obtained through flexible docking regardless of the initial protein conformation. Finally, the stability of generated docking poses was verified by molecular dynamic simulations. Accurate binding mode prediction was obtained showing that the herein reported approach is a highly promising combination of in silico methods able to rightly predict the binding mode of small molecule ligands in flexible binding pockets, such as those observed in some reader proteins.Publikationsfonds ML

New model to estimate daily global solar radiation over Nigeria

This study focussed on developing an appropriate model for estimating daily global solar radiation for any location in Nigeria. Data for the study were obtained from the Nigeria Meteorological Agency, covering 12 sites, spread across the six geopolitical zones, for a period between 1987 and 2010. Various statistical methods were employed to determine the performance and accuracy of the model. A multivariate model that expresses global solar irradiance in terms of location latitude, daily relative sunshine, maximum daily temperature, daily average relative humidity, and cosine of day number was developed. The inclusion of the maximum daily temperature and daily mean relative humidity makes the model much more sensitive to climatic and weather changes. Also, the seasonal fluctuations of the humid tropical region are also well captured in the model. The analysis showed a good agreement between the measured data and computed results. Thus the model can be used to predict the global solar irradiance over Nigeria with minimum error. Further to this, the global solar radiation intensity values produced by this approach can be used in the design and estimation of the performance of solar applications

Le décalage entre la communication sociétale et les pratiques de l'entreprise : le cas de l'intérim

The temporary employment sector has greatly democratized in recent decades and generates numerous negative externalities for civil society. Indeed, the temporary employment sector is a source of social vulnerability for the temporary workers, in a society where individuals are socially integrated through their jobs. The temporary employment sector contributes in the precarious of life and work conditions, relegation and social exclusion. To limit these social deviations and internalize societal issues, the temporary work companies (TWC) are encouraged, through extra-financial reporting, to engage in CSR. The TWC value their commitment through a voluntary social communication, which is based in particular on the production of a CSR/Sustainable Development report. The societal communication vehicle commitments by TWC to protect the temporary workers’s interests. The objectives of social communication are numerous : improve the image and the reputation, promote self-regulation activities, allowing continuous access to temporary resources, reduce supervision activities by public authorities, legitimize the existence of ETT despite these negative externalities, generate positive attitudes of stakeholders, contribute to the overall performance and reduce hidden costs due to the staff turnover. The CSR commitment must be deployed within the TWC and arouse the collective membership of the internal stakeholders. However, the academic literature on the CSR commitment in the temporary employment sector is a gap between social communication and the actual practices of TWC. In contrast, this gap causes the opposite effect and generates negative attitudes of stakeholders towards TWC. Given these challenges, the lack of information in the academic literature and the lack of empirical studies on the gap between social communication and the actual practices of TWC led us to formulate our overall research problem. Our research aim to make significant contributions in this emerging area of research.Le secteur de l’intérim s’est fortement démocratisé ces dernières décennies et génère de nombreuses externalités négatives pour la société civile. En effet, l’intérim est source de vulnérabilité sociale pour les intérimaires, dans une société où les individus s'intègrent socialement à travers leur emploi. L’intérim contribue à la précarisation des conditions de vie et de travail, à la relégation et à l’exclusion sociale. Pour limiter ces dérives sociales et internaliser les problématiques sociétales, les entreprises de travail temporaire (ETT) sont incitées, à travers le reporting extra-financier, à s’engager dans une démarche RSE. Les ETT valorisent leur engagement à travers une communication sociétale volontaire, qui repose notamment sur la production d’un rapport RSE/Développement Durable. La communication sociétale véhicule les engagements pris par les ETT pour protéger les intérêts des intérimaires. Les objectifs de la communication sociétale sont multiples : améliorer l’image et la réputation, favoriser l’autorégulation des activités, permettre un accès continu aux ressources intérimaires, diminuer l’encadrement des activités par les pouvoirs publics, légitimer l’existence des ETT malgré ces externalités négatives, générer une attitude positive des parties prenantes, contribuer à la performance globale et diminuer les coûts cachés relatifs au turn-over du personnel. L’engagement RSE doit être déployé au sein des ETT et susciter l’adhésion collective des parties prenantes internes. Cependant, la littérature académique relative à l’engagement RSE dans le secteur de l’intérim relève un décalage entre la communication sociétale et les pratiques réelles des ETT. Par contraste, ce décalage provoque des effets inverses et génère une attitude négative des parties prenantes envers les ETT. Compte tenu de ces enjeux, le manque d’informations dans la littérature académique ainsi que l’absence d’études empiriques relatives au décalage entre la communication sociétale et les pratiques réelles des ETT nous ont conduits à formuler notre problématique de recherche générale. Nos travaux de recherche ont pour objectif d’apporter des contributions significatives dans ce domaine de recherche émergent

Muscle carnitine palmitoyltransferase II deficiency : a review of enzymatic controversy and clinical features

CPT (carnitine palmitoyltransferase) II muscle deficiency is the most common form of muscle fatty acid metabolism disorders. In contrast to carnitine deficiency, it is clinically characterized by attacks of myalgia and rhabdomyolysis without persistent muscle weakness and lipid accumulation in muscle fibers. The biochemical consequences of the disease-causing mutations are still discussed controversially. CPT activity in muscles of patients with CPT II deficiency ranged from not detectable to reduced to normal. Based on the observation that in patients, total CPT is completely inhibited by malony-CoA, a deficiency of malonyl-CoA-insensitive CPT II has been suggested. In contrast, it has also been shown that in muscle CPT II deficiency, CPT II protein is present in normal concentrations with normal enzymatic activity. However, CPT II in patients is abnormally sensitive to inhibition by malonyl-CoA, Triton X-100 and fatty acid metabolites. A recent study on human recombinant CPT II enzymes (His6-N-hCPT2 and His6-N-hCPT2/S113L) revealed that the wild-type and the S113L variants showed the same enzymatic activity. However, the mutated enzyme showed an abnormal thermal destabilization at 40 and 45 °C and an abnormal sensitivity to inhibition by malony-CoA. The thermolability of the mutant enzyme might explain why symptoms in muscle CPT II deficiency mainly occur during prolonged exercise, infections and exposure to cold. In addition, the abnormally regulated enzyme might be mostly inhibited when the fatty acid metabolism is stressed

Climate change and anthropogenic intervention impact on the hydrologic anomalies in a semi-arid area : lower Zab river basin, Iraq

Climate change impact, drought phenomena and anthropogenic stress are of increasing apprehension for water resource managers and strategists, particularly in arid regions. The current study proposes a generic methodology to evaluate the potential impact of such changes at a basin scale. The Lower Zab River Basin located in the north of Iraq has been selected for illustration purposes. The method has been developed through evaluating changes during normal hydrological years to separate the effects of climate change and estimate the hydrologic abnormalities utilising Indicators of Hydrologic Alteration. The meteorological parameters were perturbed by applying adequate delta perturbation climatic scenarios. Thereafter, a calibrated rainfall-runoff model was used for streamflow simulations. Findings proved that climate change has a more extensive impact on the hydrological characteristics of the streamflow than anthropogenic intervention (i.e. the construction of a large dam in the catchment). The isolated baseflow is more sensitive to the precipitation variations than to the variations of the potential evapotranspiration. The current hydrological anomalies are expected to continue. This comprehensive basin study demonstrates how climate change impact, anthropogenic intervention as well as hydro-climatic drought and hydrological anomalies can be evaluated with a new methodology

Fatty acid binding to the human transport proteins FABP3, FABP4, and FABP5 from a Ligand’s perspective

Fatty acid binding proteins (FABPs) are a family of amphiphilic transport proteins with high diversity in terms of their amino acid sequences and binding preferences. Beyond their main biological role as cytosolic fatty acid transporters, many aspects regarding their binding mechanism and functional specializations in human cells remain unclear. In this work, the binding properties and thermodynamics of FABP3, FABP4, and FABP5 were analyzed under various physical conditions. For this purpose, the FABPs were loaded with fatty acids bearing fluorescence or spin probes as model ligands, comparing their binding affinities via microscale thermophoresis (MST) and continuous-wave electron paramagnetic resonance (CW EPR) spectroscopy. The CW EPR spectra of non-covalently bound 5- and 16-DOXYL stearic acid (5/16-DSA) deliver in-depth information about the dynamics and chemical environments of ligands inside the binding pockets of the FABPs. EPR spectral simulations allow the construction of binding curves, revealing two different binding states (‘intermediately’ and ‘strongly’ bound). The proportion of bound 5/16-DSA depends strongly on the FABP concentration and the temperature but with remarkable differences between the three isoforms. Additionally, the more dynamic state (‘intermediately bound’) seems to dominate at body temperature with thermodynamic preference. The ligand binding studies were supplemented by aggregation studies via dynamic light scattering and bioinformatic analyses. Beyond the remarkably fine-tuned binding properties exhibited by each FABP, which were discernible with our EPR-centered approach, the results of this work attest to the power of simple spectroscopic experiments to provide new insights into the ligand binding mechanisms of proteins in general on a molecular level

Comparative structure-based virtual screening utilizing optimized AlphaFold Model identifies selective HDAC11 inhibitor

HDAC11 is a class IV histone deacylase with no crystal structure reported so far. The catalytic domain of HDAC11 shares low sequence identity with other HDAC isoforms, which makes conventional homology modeling less reliable. AlphaFold is a machine learning approach that can predict the 3D structure of proteins with high accuracy even in absence of similar structures. However, the fact that AlphaFold models are predicted in the absence of small molecules and ions/cofactors complicates their utilization for drug design. Previously, we optimized an HDAC11 AlphaFold model by adding the catalytic zinc ion and minimization in the presence of reported HDAC11 inhibitors. In the current study, we implement a comparative structure-based virtual screening approach utilizing the previously optimized HDAC11 AlphaFold model to identify novel and selective HDAC11 inhibitors. The stepwise virtual screening approach was successful in identifying a hit that was subsequently tested using an in vitro enzymatic assay. The hit compound showed an IC50 value of 3.5 µM for HDAC11 and could selectively inhibit HDAC11 over other HDAC subtypes at 10 µM concentration. In addition, we carried out molecular dynamics simulations to further confirm the binding hypothesis obtained by the docking study. These results reinforce the previously presented AlphaFold optimization approach and confirm the applicability of AlphaFold models in the search for novel inhibitors for drug discovery