Abstract: The search and development of anti-HIV drugs is currently one of themost urgent tasks of pharmacological studies. In this work, a quantitative structure-activity relationship (QSAR) model based on some new norm indexes, was obtained to a series ofmore than 150 HEPT derivatives (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine) to find their pEC₅₀ (the required effective concentration to achieve 50% protection ofMT-4 cells against the cytopathic effect of virus) and pCC₅₀ (the required cytotoxic concentration to reduce visibility of 50% mock infected cell) activities. The model efficiencies were then validated using the leave-one-out cross validation (LOO-CV) and yrandomization test. Results indicated that this new model was efficient and could provide satisfactory results for prediction of pEC₅₀ and pCC₅₀ with the higher R_train² and the higher R_test². By using the leverage approach, the applicability domain of this model was further investigated and no response outlier was detected for HEPT derivatives involved in this work. Comparison results with reference methods demonstrated that this new method could result in significant improvements for predicting pEC₅₀ and pCC₅₀ of anti-HIV HEPT derivatives. Moreover, results shown in this present study suggested that these two absolutely different activities pEC₅₀ and pCC₅₀ of anti-HIV HEPT derivatives could be predicted well with a totally similar QSAR model, which indicated that this model might have the potential to be further utilized for other biological activities of HEPT derivatives.

Key words: Mathematical modeling, Structure-activity relationship, Pharmaceuticals, HEPT derivatives, Anti-HIV-1 activity, Prediction

摘要： The search and development of anti-HIV drugs is currently one of themost urgent tasks of pharmacological studies. In this work, a quantitative structure-activity relationship (QSAR) model based on some new norm indexes, was obtained to a series ofmore than 150 HEPT derivatives (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine) to find their pEC₅₀ (the required effective concentration to achieve 50% protection ofMT-4 cells against the cytopathic effect of virus) and pCC₅₀ (the required cytotoxic concentration to reduce visibility of 50% mock infected cell) activities. The model efficiencies were then validated using the leave-one-out cross validation (LOO-CV) and yrandomization test. Results indicated that this new model was efficient and could provide satisfactory results for prediction of pEC₅₀ and pCC₅₀ with the higher R_train² and the higher R_test². By using the leverage approach, the applicability domain of this model was further investigated and no response outlier was detected for HEPT derivatives involved in this work. Comparison results with reference methods demonstrated that this new method could result in significant improvements for predicting pEC₅₀ and pCC₅₀ of anti-HIV HEPT derivatives. Moreover, results shown in this present study suggested that these two absolutely different activities pEC₅₀ and pCC₅₀ of anti-HIV HEPT derivatives could be predicted well with a totally similar QSAR model, which indicated that this model might have the potential to be further utilized for other biological activities of HEPT derivatives.

关键词: Mathematical modeling, Structure-activity relationship, Pharmaceuticals, HEPT derivatives, Anti-HIV-1 activity, Prediction