Ab initio molecular dynamics study of water oxidation reaction pathways in mono-Ru catalysts.

Ab initio molecular dynamics simulations with an adaptive biasing potential are carried out to study the reaction path in mononuclear Ru catalysts for water oxidation of the type [(Ar)Ru(X)(bpy)](+) with different aromatic ligands (Ar). The critical step of the O-O bond formation in the catalytic cycle starting from the [(Ar)Ru(O)(bpy)](2+) intermediate is analyzed in detail. It is shown that an explicit inclusion of the solvent environment is essential for a realistic description of the reaction path. Clear evidence is presented for a concerted reaction in which the O-O bond formation is quickly followed by a proton transfer leading to a Ru-OOH intermediate and a hydronium ion. An alternative path in which the approaching water first coordinates to the metal centre is also investigated, and it is found to induce a structural instability of the catalyst with the breaking of the aromatic ligand coordination bond.

Identification of potent and selective glucosylceramide synthase inhibitors from a library of N-alkylated iminosugars.

Glucosylceramide synthase (GCS) is an important target for clinical drug development for the treatment of lysosomal storage disorders and a promising target for combating type 2 diabetes. Iminosugars are useful leads for the development of GCS inhibitors; however, the effective iminosugar type GCS inhibitors reported have some unwanted cross-reactivity toward other glyco-processing enzymes. In particular, iminosugar type GCS inhibitors often also inhibit to some extent human acid glucosylceramidase (GBA1) and the nonlysosomal glucosylceramidase (GBA2), the two enzymes known to process glucosylceramide. Of these, GBA1 itself is a potential drug target for the treatment of the lysosomal storage disorder, Gaucher disease, and selective GBA1 inhibitors are sought after as potential chemical chaperones. The physiological importance of GBA2 in glucosylceramide processing in relation to disease states is less clear, and here, selective inhibitors can be of use as chemical knockout entities. In this communication, we report our identification of a highly potent and selective N-alkylated l-ido-configured iminosugar. In particular, the selectivity of 27 for GCS over GBA1 is striking.