New consensus multivariate models based on PLS and ANN studies of sigma-1 receptor antagonists

Abstract

The treatment of neuropathic pain is very complex and there are few drugs approved for this purpose. Among the studied compounds in the literature, sigma-1 receptor antagonists have shown to be promising. In order to develop QSAR studies applied to the compounds of 1-arylpyrazole derivatives, multivariate analyses have been performed in this work using partial least square (PLS) and artificial neural network (ANN) methods. A PLS model has been obtained and validated with 45 compounds in the training set and 13 compounds in the test set (r²_training = 0.761, q² = 0.656, r²_test = 0.746, MSE_test = 0.132 and MAE_test = 0.258). Additionally, multi-layer perceptron ANNs (MLP-ANNs) were employed in order to propose non-linear models trained by gradient descent with momentum backpropagation function. Based on MSE_test values, the best MLP-ANN models were combined in a MLP-ANN consensus model (MLP-ANN-CM; r²_test = 0.824, MSE_test = 0.088 and MAE_test = 0.197). In the end, a general consensus model (GCM) has been obtained using PLS and MLP-ANN-CM models (r²_test = 0.811, MSE_test = 0.100 and MAE_test = 0.218). Besides, the selected descriptors (GGI6, Mor23m, SRW06, H7m, MLOGP, and μ) revealed important features that should be considered when one is planning new compounds of the 1-arylpyrazole class. The multivariate models proposed in this work are definitely a powerful tool for the rational drug design of new compounds for neuropathic pain treatment. Graphical abstract Main scaffold of the 1-arylpyrazole derivatives and the selected descriptors.

Keywords: 1-arylpyrazole; Consensus modeling; MLP-ANN; PLS; QSAR; Sigma-1 receptor.