No abstract

Four novel proteasome inhibitors, TMC-95A-D (1-4) have been isolated from the fermentation broth of Apiospora montagnei Sacc. TC 1093, isolated from a soil sample. All of the molecular formulas of 1-4 were established as C(33)H(38)N(6)O(10) by high-resolution FAB-MS. Their planar structures were determined on the basis of extensive analyses of 1D and 2D NMR, and degradation studies. Compounds 1-4 have the same planar structures to each other, and are unique highly modified cyclic peptides containing L-tyrosine, L-aspargine, highly oxidized L-tryptophan, (Z)-1-propenylamine, and 3-methyl-2-oxopentanoic acid units. The absolute configuration at C-11 and C-36 of 1-4 was determined based on chiral TLC and HPLC analyses of their chemical degradation products. The ROESY analysis along with (1)H-(1)H coupling constants clarified the absolute stereochemistry at C-6, -7, -8, and -14 of the cyclic moieties. These studies revealed the relationships of 1-4 to be diastereomers at C-7 and C-36.

No abstract

Two virtual screening strategies, "query by bagging" (QBag) and "query by bagging with descriptor-sampling" (QBagDS), based on active learning were devised. The QBag strategy generates multiple structure-activity relationship rules by bagging and selects compounds to improve the rules. To find many structurally diverse hits, the QBagDS strategy generates rules by bagging with descriptor sampling. They can also use prior knowledge about hits to improve the efficiency at the beginning of screening. We performed simulation experiments and clustering analysis for several G-protein coupled receptors and showed that the QBag and QBagDS strategies outperform the conventional similarity-based strategy and that using both descriptor sampling and prior knowledge are effective for finding many hits. We applied the bagging with descriptor sampling strategy to novel hit finding, and 4 of the 10 selected compounds showed high inhibition.

A rationally designed donor–acceptor conjugate efficiently generates a photoinduced charge-separated state in a cellular environment, achieving photoinduction of neuronal firing.