Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice

Natural and anthropogenic changes to mangrove distributions in the Pioneer River Estuary (QLD, Australia)

We analyzed a time series of aerial photographs and Landsat satellite imagery of the Pioneer River Estuary (near Mackay, Queensland, Australia) to document both natural and anthropogenic changes in the area of mangroves available to filter river runoff between 1948 and 2002. Over 54 years, there was a net loss of 137 ha (22%) of tidal mangroves during four successive periods that were characterized by different driving mechanisms: (1) little net change (1948– 1962); (2) net gain from rapid mangrove expansion (1962–1972); (3) net loss from clearing and tidal isolation (1972–1991); and (4) net loss from a severe species-specific dieback affecting over 50% of remaining mangrove cover (1991–2002). Manual digitization of aerial photographs was accurate for mapping changes in the boundaries of mangrove distributions, but this technique underestimated the total loss due to dieback. Regions of mangrove dieback were identified and mapped more accurately and efficiently after applying the Normalized Difference Vegetation Index (NDVI) to Landsat Thematic Mapper satellite imagery, and then monitoring changes to the index over time. These remote sensing techniques to map and monitor mangrove changes are important for identifying habitat degradation, both spatially and temporally, in order to prioritize restoration for management of estuarine and adjacent marine ecosystems

Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock

<p>Abstract</p> <p>Background</p> <p>Molecular docking methods are commonly used for predicting binding modes and energies of ligands to proteins. For accurate complex geometry and binding energy estimation, an appropriate method for calculating partial charges is essential. AutoDockTools software, the interface for preparing input files for one of the most widely used docking programs AutoDock 4, utilizes the Gasteiger partial charge calculation method for both protein and ligand charge calculation. However, it has already been shown that more accurate partial charge calculation - and as a consequence, more accurate docking- can be achieved by using quantum chemical methods. For docking calculations quantum chemical partial charge calculation as a routine was only used for ligands so far. The newly developed Mozyme function of MOPAC2009 allows fast partial charge calculation of proteins by quantum mechanical semi-empirical methods. Thus, in the current study, the effect of semi-empirical quantum-mechanical partial charge calculation on docking accuracy could be investigated.</p> <p>Results</p> <p>The docking accuracy of AutoDock 4 using the original AutoDock scoring function was investigated on a set of 53 protein ligand complexes using Gasteiger and PM6 partial charge calculation methods. This has enabled us to compare the effect of the partial charge calculation method on docking accuracy utilizing AutoDock 4 software. Our results showed that the docking accuracy in regard to complex geometry (docking result defined as accurate when the RMSD of the first rank docking result complex is within 2 Å of the experimentally determined X-ray structure) significantly increased when partial charges of the ligands and proteins were calculated with the semi-empirical PM6 method.</p> <p>Out of the 53 complexes analyzed in the course of our study, the geometry of 42 complexes were accurately calculated using PM6 partial charges, while the use of Gasteiger charges resulted in only 28 accurate geometries. The binding affinity estimation was not influenced by the partial charge calculation method - for more accurate binding affinity prediction development of a new scoring function for AutoDock is needed.</p> <p>Conclusion</p> <p>Our results demonstrate that the accuracy of determination of complex geometry using AutoDock 4 for docking calculation greatly increases with the use of quantum chemical partial charge calculation on both the ligands and proteins.</p

Mapping and Assessing the Land Cover and Land Use of a fragile Coastal Landscape, Cuddalore District, Tamil Nadu, South India

International audienc

Canopy Texture Analysis for Large-Scale Assessments of Tropical Forest Stand Structure and Biomass

International audienc

Treetops at risk : challenges of global canopy

The structural organization of a forest canopy is an important descriptor that may provide spatial information for vegetation mapping and management planning, such as attributes of plant species distributions, intensity of disturbances, aboveground biomass or carbon stock. A variety of airborne and satellite images characterize forest stands from above the canopy, providing the advantage of a rapid exploration of extensive and sometimes inaccessible zones. Unfortunately, this approach has limited applicability in wet tropical regions, because most optical and radar signals that deliver medium to high spatial resolution data will saturate at intermediate levels of biomass ranges (ca. 150200 t.ha&#8722;1) or leaf area index values (Gibbs et al. 2007). As a consequence, while forest vs. non-forest classifications are nowadays routinely performed from such data, variations in stand structure and biomass within forests of fairly closed canopy remain almost undetectable with classical techniques, and the forest treetops seen from above appear as a homogeneously undulating green carpet. However, rainforest structure varies substantially from place to place either naturally (as the soil, composition or forest dynamics vary) or from anthropogenic degradations. Detecting, characterizing and mapping these variations over vast areas are critical to emerging policies, such as the REDD+ agenda (Maniatis and Mollicone 2010), whereby participating countries will monitor their carbon stock variation. Although promising technology such as LiDAR (light detection and ranging) has great potential, they remain very expensive to systematically assess large expanses of tropical forests (but see Asner et al. 2010). We propose as a cost-effective alternative canopy grain texture analysis from very-high-resolution air- or space-borne images, which proved efficient for retrieving and mapping stand structure parameters including aboveground biomass over vast poorly documented areas of tropical forest

Chest CT findings in idiopathic and heritable pediatric pulmonary arterial hypertension

ObjectivesTo describe CT findings in paediatric idiopathic pulmonary arterial hypertension (PAH).MethodsLung and cardiac CT of 30 children with idiopathic PAH or heritable PAH (median age 7.5years [range 11months–15.5years]) were compared to 30 children without cardiac or lung disease matched for age. PAH diagnosis was always confirmed by a right heart catheterization. All patients were considered as having idiopathic or heritable PAH after a complete diagnostic work-up according to the Nice international recommendations. Seven/30 patients had mutations in one of the known PAH genes (BMPR2, Alk1, TBX4, EIF2AK4).ResultsCT findings were significant increase of the ratio of main pulmonary artery/ascending aorta (median 1.5 [1–1.9] versus 0.98 [0.7–1.1] in controls and of right ventricle/left ventricle (median 1.4 [0.9–3] versus 0.8 [0.6–1]). Mediastinal adenopathies were observed in 9 cases. Parenchymal anomalies were present in 25/30 patients with mosaic pattern of attenuation in 9, ground glass nodules in 17, micronodules in 12, interlobular septal thickening in 13, consolidation in 3, and distal pulmonary arteries anomalies in 16. No correlation was found between CT findings and WHO functional class or hemodynamic characteristics of patients. Veno-occlusive disease was diagnosed at CT in 3 patients and confirmed subsequently either genetically or histologically. Two/4 diagnoses of Rendu-Osler (ALK1 mutations) were diagnosed at CT before genetic confirmation.ConclusionCT is a valuable tool in the diagnostic work-up of PAH in children. Specific parenchymal anomalies are highly suggestive of EIF2AK4 or ALK1 mutations and may orientate genetic confirmation of the disease

Dynamique des mangroves à partir de la télédétection optique à très haute résolution spatiale

International audienceAssessing the role of tropical forests in biogeochemical cycles is one of the greatest scientific challenges of the century. The impact of climate change could increase the mortality of tropical forests and decrease their ability to store atmospheric carbon dioxide. Efforts to model the forest dynamics in these regions are hindered by the lack of ground measurements and the spatial-temporal overlap of function management processes. Some of the models developed attempt to show the environment’s influence on forest dynamics, particularly by studying the capacity for canopy deformation (plasticity of the crown), as explained in Purves et al. The models allow us to better understand the development of intertree competition, the capacity of species to adapt to changes and how the forest functions as a whole.L'évaluation du rôle des forêts tropicales dans les cycles biogéochimiques est l'un des plus grands défis scientifiques du siècle. L'impact du changement climatique pourrait accroître la mortalité des forêts tropicales et diminuer leur capacité à stocker le dioxyde de carbone atmosphérique. Les efforts visant à modéliser la dynamique forestière dans ces régions sont entravés par l'absence de mesures au sol et le chevauchement spatio-temporel des processus de gestion des fonctions. Certains des modèles développés tentent de montrer l'influence de l'environnement sur la dynamique des forêts, en particulier en étudiant la capacité de déformation de la canopée (plasticité de la couronne), comme expliqué dans Purves et al. Les modèles nous permettent de mieux comprendre le développement de la compétition entre individus, la capacité des espèces à s'adapter aux changements et comment la forêt fonctionne dans son ensemble