Monte Carlo method based QSAR modeling of maleimide derivatives as glycogen synthase kinase-3ß inhibitors.

The Monte Carlo method was used for QSAR modeling of maleimide derivatives as glycogen synthase kinase-3ß inhibitors. The first QSAR model was developed for a series of 74 3-anilino-4-arylmaleimide derivatives. The second QSAR model was developed for a series of 177 maleimide derivatives. QSAR models were calculated with the representation of the molecular structure by the simplified molecular input-line entry system. Two splits have been examined: one split into the training and test set for the first QSAR model, and one split into the training, test and validation set for the second. The statistical quality of the developed model is very good. The calculated model for 3-anilino-4-arylmaleimide derivatives had following statistical parameters: r(2)=0.8617 for the training set; r(2)=0.8659, and r(m)(2)=0.7361 for the test set. The calculated model for maleimide derivatives had following statistical parameters: r(2)=0.9435, for the training, r(2)=0.9262 and r(m)(2)=0.8199 for the test and r(2)=0.8418, r(av)(m)(2)=0.7469 and ∆r(m)(2)=0.1476 for the validation set. Structural indicators considered as molecular fragments responsible for the increase and decrease in the inhibition activity have been defined. The computer-aided design of new potential glycogen synthase kinase-3ß inhibitors has been presented by using defined structural alerts.

Aflatoxin B1-induced changes of glutathione-S-transferase activity in the plasma and liver of the rat.

BACKGROUND: The influence of low doses of aflatoxin B1(AFB1) and partial hepatectomy (PH) on glutathione-S-transferase (GST) activity was studied in the plasma and liver of the rat. METHODS: The animals were divided into four groups. The first (I) and the second (II) group were treated with AFB1 freshly dissolved in dimethyl sulphoxide (DMSO), and administered as a single intraperitoneal dose of 50 micrograms/rat 24 hrs after the rats had undergone either sham operation or, 40% PH, respectively. The third group (III) of animals was treated with a total dose of 1 mg AFB1-5 days per week during a period of 8 weeks. The non-treated animals were used as controls (C). RESULTS: We observed a significant increase of GST activity in the plasma of all experimental groups compared to the controls (C), (p < 0.02 to p < 0.005). In the liver, the GST activity of all experimental groups was also significantly increased, compared to the controls (from p < 0.02 to p < 0.005). CONCLUSION: The administration of both single and multiple doses of AFB1 led to long term increase of GST activity in the rat plasma and liver, and partial hepatectomy had no significant effect on this phenomenon.