Modeling of activity of cyclic urea HIV-1 protease inhibitors using regularized-artificial neural networks

Artificial neural networks (ANNs) were used to model both inhibition of HIV-1 protease (K-i) and inhibition of HIV replication (IC90) for 55 Cyclic Urea derivatives using constitutional and 2D descriptors. As a preliminary step, linear dependences were established by multiple linear regression (MLR) approaches, selecting the relevant descriptors by genetic algorithm (GA) feature selection. For ANN models non-linear GA feature selection was also applied. Non-linear modeling of K-i overcame the results of the linear one using four properties, keeping in mind standard Pearson R correlation coefficients (0.931 vs. 0.862) and leave one out (LOO) cross-validation analysis (Q(LOO)(2) = 0.703 vs. 0.510). Oil the other hand, IC90 modeling was insoluble by a linear L approach: no predictive model was achieved; however, a non-linear relation was encountered according to statistic results (R = 0.891; Q(LOO)(2) = 0.568). The best non-linear models suggested the influence of the presence of nitrogen atoms and the molecular Volume distribution in the inhibitor structures oil the HIV-1 protease inhibition as well as that the inhibition of HIV replication was dependent on the occurrence of five-member rings. Finally, inhibitors were well distributed regarding its activity levels in a Kohonen self-organizing map built using the input variables of the best non-linear models. (c) 2005 Elsevier Ltd. All rights reserved.