Dodson Blake (collaroption17)

Different strategies have been explored to combine the information provided by docking and similarity measurements for re-ranking the screened ligands. For a benchmarking of 44 datasets, including 41 targets, the hybrid methods increase the identification of active compounds, according to the early (ROCe%) and total (AUC) enrichment metrics of VS, compared to pure LB and SB methods. Finally, the hybrid approaches are also more effective in enhancing the chemical diversity of active compounds. The datasets employed in this work are available in https//github.com/Pharmacelera/Molecular-Similarity-and-Docking.A robust general route to lanthanide dicyanamide (DCA-) complexes has been developed where f-element salts are dissolved in DCA--based ionic liquids (ILs) directly or formed in situ, forcing coordination of these normally weakly coordinating soft N-donor anions, even in an ambient, non-moisture-excluding environment. A series of lanthanide complexes [C2mim][Ln(DCA)4(H2O)4] (C2mim = 1-ethyl-3-methylimidazolium; Ln = La, Nd, Eu, Tb, Dy, and Yb) and [C2mim]3n[La(OH2)4(μ2-DCA)4]n[La(OH2)2(μ3-DCA)3(μ2-DCA)4]2n(Cl)4n were crystallized under a variety of conditions using this methodology and structurally characterized using single crystal X-ray diffraction. Although not all examples were isostructural, the dominant feature across the series was the presence of [Ln(DCA)4(H2O)4]- anionic nodes with all terminal DCA- ligands accepting hydrogen bonds from the coordinated water molecules forming a 3D metal organic framework. To determine if any structural clues might aid in the further development of the synthetic methodology, the metal-free IL [C1mim][DCA] (C1mim = 1,3-dimethylimidazolium), a room-temperature solid, crystalline analogue of the reaction IL, which is liquid at room temperature, was also prepared and structurally characterized. The ready isolation of these compounds allowed us to begin an investigation of the physical properties such as the luminescence at room and low temperatures for the Eu, Tb, and Dy representatives.To assess ecological risks from chemical exposure we need tools to extrapolate from the sublethal effects observed in the laboratory under constant exposure to realistic time-varying exposures. Dynamic energy budget theory offers a mechanistic modelling approach to describe the entire life-history of a single organism and the effects of toxicant exposure. We use a simplified model which can be wholly calibrated from standard chronic bioassay data. Case-studies on standard test organisms (Americamysis bahia and Pimephales promelas) are presented to demonstrate the calibration procedure, and in the second case data are available to pseudo-validate model performance. We use these results to highlight gaps and shortcomings in the current state of the science, and we discuss how these can be overcome to maximize the potential of DEB theory in ecological risk assessment.Approximately 95% of human genes are alternatively spliced, and aberrant splicing events can cause disease. One pre-mRNA that is alternatively spliced and linked to neurodegenerative diseases is tau (microtubule-associated protein tau), which can cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and can contribute to Alzheimer's disease. Here, we describe the design of structure-specific lead small molecules that directly target tau pre-mRNA from sequence. This was followed by hit expansion and analogue synthesis to further improve upon these initial lead molecules. The emergent compounds were assessed for functional activity in a battery of assays, including binding assays and an assay that mimics molecular recognition of tau pre-mRNA by a U1 small nuclear ribonucleoprotein (snRNP) splicing factor. Compounds that emerged from these studies had enhanced potency and selectivity for the target RNA relative to the initial hits, while also having significantly improved drug-like properties. The compounds are shown to