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Abstract: Structure-guided drug discovery emerged in the 1970s and 1980s, stimulated by the three-dimensional structures of protein targets that became available, mainly through X-ray crystal structure analysis, assisted by the development of synchrotron radiation sources. Structures of known drugs or inhibitors were used to guide the development of leads. The growth of high-throughput screening during the late 1980s and the early 1990s in the pharmaceutical industry of chemical libraries of hundreds of thousands of compounds of molecular weight of approximately 500 Da was impressive but still explored only a tiny fraction of the chemical space of the predicted 1040 drug-like compounds. The use of fragments with molecular weights less than 300 Da in drug discovery not only decreased the chemical space needing exploration but also increased promiscuity in binding targets. Here we discuss advances in X-ray fragment screening and the challenge of identifying sites where fragments not only bind but can be chemically elaborated while retaining their positions and binding modes. We first describe the analysis of fragment binding using conventional X-ray difference Fourier techniques, with Mycobacterium abscessus SAICAR synthetase (PurC) as an example. We observe that all fragments occupy positions predicted by computational hotspot mapping. We compare this with fragment screening at Diamond Synchrotron Light Source XChem facility using PanDDA software, which identifies many more fragment hits, only some of which bind to the predicted hotspots. Many low occupancy sites identified may not support elaboration to give adequate ligand affinity, although they will likely be useful in drug discovery as ‘warm spots’ for guiding elaboration of fragments bound at hotspots. We discuss implications of these observations for fragment screening at the synchrotron sources.

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Abstract: The understanding of the gypsum (CaSO4∙2H2O) formation pathway from aqueous solutions has been the subject of intensive research in the last couple of years. This interest stems from the fact that gypsum appears to fall into a broader category of crystalline materials whose formation does not follow classical nucleation and growth theories. The pathways involve transitory precursor cluster species, yet the actual structural properties of such clusters are not very well understood. Here, we show how in situ high-energy X-ray diffraction (HEXD) experiments and molecular dynamics (MD) simulations can be combined to derive the structure of small CaSO4 clusters, which are precursors to crystalline gypsum. We fitted several plausible structures to the derived pair distribution functions (PDFs), and explored their dynamic properties using unbiased MD based on both rigid-ion and polarizable force-fields. Determination of the structure and (meta)stability of the primary species is important both from a fundamental and applied perspective; for example, this will allow for improved design of additives for greater control of the nucleation pathway.

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Abstract: 6,6′,13,13′- tetrahydro-6,6′-bipentacene (HBP), the intermediate molecule connecting pentacene to previously observed peripentacene and extended pentacene oligomers through the formation of a carbon-carbon bond, is synthesised and crystallographically characterised. Heating pentacene to 300 ºC under vacuum for 200 hours results in pale golden crystals of HBP and amorphous material containing pentacene oligomers, offering experimental evidence that pentacene preferentially dimerises at the 6,6′- position. Continued heating of HBP results in co-crystals of 6,13-dihydrogenated pentacene (HP) and pentacene and further amorphous pentacene oligomers. The amorphous material consists of layered carbonaceous species with a graphenic nature, as determined by Raman spectroscopy and electron microscopy, and suggests HBP as an intermediate to hydrogenated pentacene species and pentacene oligomers, such as peripentacene, of interest in organic electronics.

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Abstract: On cooling to 229 K at ambient pressure, 2,2,2-trifluoroethanol freezes to form a crystal structure characterised by hydrogen-bonded molecular chains in the orthorhombic space group Pca21 (form 1). On compression to 0.22 GPa at room temperature, however, liquid 2,2,2-trifluoroethanol crystallises in a structure adopting triclinic P symmetry (form 2). Although the form 1 and form 2 polymorphs are both characterised by the formation of hydrogen-bonded chains, the arrangement of the molecules within the chains are significantly different with the high-pressure form appearing to adopt a more strained configuration. The orientation of the molecules in form 2 is such that the hydrogen bonds in neighbouring chains are in close proximity with a bridging interchain O⋯O contact distance that is of the same order as the O⋯O distances found for the hydrogen bonds. The resulting close pairing of neighbouring catemeric chains produces molecular pillars in the structure of form 2.

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Abstract: Reaction between CaMn0.5Ir0.5O3 and NaH, either through solid-solid contact or via a gas mediated reaction process, yields the topochemically reduced phase CaMn0.5Ir0.5O2.5 in which Mn3+ and Ir3+ cations are located within a partially anion-vacancy disordered lattice. Magnetization data from CaMn0.5Ir0.5O2.5 can be fit by the Curie–Weiss law to yield C = 1.586 cm3 K mol–1 and θ = −86.9 K, consistent with a combination of S = 2, Mn3+ and S = 0, Ir3+. On cooling below T ∼ 110 K, the system undergoes a transition to a spin-glass state, consistent with the observed Mn/Ir cation disorder and frustration between Mn-O-Mn and Mn-O-Ir-O-Mn magnetic couplings. The degree of reduction and the observed anion-vacancy disorder are discussed on the basis of the d-orbital filling of the transition-metal cations.