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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 series of spiro[imidazolidine-4,4'(1'H)-quinazoline]- 2,2'5(3'H)-triones were prepared and tested for aldose reductase inhibitory activity. The 6'-halogenated derivatives were found to be highly potent in vitro inhibitors of male rabbit lens aldose reductase and in vivo inhibitors of polyol accumulation in the sciatic nerves of galactosemic rats. Of these, (4R)-6'-chloro-3'-methylspiro[imidazolidine-4,4'(1'H)-quinazoline] -2,2',5(3'H)-trione (67) showed the most potent in vitro and in vivo activities. An oral dose of 3 g/kg of compound 67 caused neither death nor behavioral abnormality in the preliminary acute toxicity study using mice and rats. Compound 67 was selected as a candidate for further evaluation. The quantitative structure-activity relationships in this series are also discussed.

Bitter thresholds of a total of 93 amino acids, peptides, and their derivatives were analyzed quantitatively by use of hydrophobicity parameters reported for amino acid side chains and those for the whole molecules estimated from partition coefficients obtained experimentally. We also explored the steric parameters that best explained the variation in the intensity of bitterness attributable to the molecular shape. The results showed that the total length along the zigzag peptide backbone chain of the molecule is an important factor. The bitterness of nonzwitterionic N-acyl and ester derivatives and that of neutral N-acyl ester derivatives were expressed by a single, common equation together with those of zwitterionic amino acids and peptides. Thus the interaction via the charge with the receptor site was probably not an indispensible factor for triggering of the bitter sensation. This study, together with earlier ones, may serve as a prototype of approaches toward unraveling structure-activity relationships of complex molecules like amino acids, peptides, and their derivatives that are of medicinal or agricultural importance.