Orbifolds and Topological Defects

We study orbifolds of two-dimensional topological field theories using defects. If the TFT arises as the twist of a superconformal field theory, we recover results on the Neveu–Schwarz and Ramond sectors of the orbifold theory, as well as bulk-boundary correlators from a novel, universal perspective. This entails a structure somewhat weaker than ordinary TFT, which however still describes a sector of the underlying conformal theory. The case of B-twisted Landau–Ginzburg models is discussed in detail, where we compute charge vectors and superpotential terms for B-type branes. Our construction also works in the absence of supersymmetry and for generalised “orbifolds” that need not arise from symmetry groups. In general, this involves a natural appearance of Hochschild (co)homology in a 2-categorical setting, in which among other things we provide simple presentations of Serre functors and a further generalisation of the Cardy condition.     

A comparative study of fragment screening methods on the p38�� kinase: new methods, new insights

The stress-activated kinase p38α was used to evaluate a fragment-based drug discovery approach using the BioFocus fragment library. Compounds were screened by surface plasmon resonance (SPR) on a Biacore(?) T100 against p38α and two selectivity targets. A sub-set of our library was the focus of detailed follow-up analyses that included hit confirmation, affinity determination on 24 confirmed, selective hits and competition assays of these hits with respect to a known ATP binding site inhibitor. In addition, functional activity against p38α was assessed in a biochemical assay using a mobility shift platform (LC3000, Caliper LifeSciences). A selection of fragments was also evaluated using fluorescence lifetime (FLEXYTE(?)) and microscale thermophoresis (Nanotemper) technologies. A good correlation between the data for the different assays was found. Crystal structures were solved for four of the small molecules complexed to p38α. Interestingly, as determined both by X-ray analysis and SPR competition experiments, three of the complexes involved the fragment at the ATP binding site, while the fourth compound bound in a distal site that may offer potential as a novel drug target site. A first round of optimization around the remotely bound fragment has led to the identification of a series of triazole-containing compounds. This approach could form the basis for developing novel and active p38α inhibitors. More broadly, it illustrates the power of combining a range of biophysical and biochemical techniques to the discovery of fragments that facilitate the development of novel modulators of kinase and other drug targets.