Extending the limitations in the prediction of PAMPA permeability with machine learning algorithms

Abstract

Gastrointestinal absorption is a key factor amongst the ADME-related (absorption, distribution, metabolism and excretion) pharmacokinetic properties; therefore, it has a major role in drug discovery and drug safety determinations. The Parallel Artificial Membrane Permeability Assay (PAMPA) can be considered as the most popular and well-known screening assay for the measurement of gastrointestinal absorption. Our study provides quantitative structure-property relationship (QSPR) models based on experimental PAMPA permeability data for almost four hundred diverse molecules, which is a great extension of the applicability of the models in the chemical space. Two- and three-dimensional molecular descriptors were applied for the model building in every case. We have compared the performance of a classical partial least squares regression (PLS) model with two major machine learning algorithms: artificial neural networks (ANN) and support vector machine (SVM). Due to the applied gradient pH in the experiments, we have calculated the descriptors for the model building at pH values of 7.4 and 6.5, and compared the effect of pH on the performance of the models. After a complex validation protocol, the best model had an R²=0.91 for the training set, and R²= 0.84 for the external test set. The developed models are capable for the robust and fast prediction of new compounds with an excellent accuracy compared to the previous QSPR models.

Keywords: Machine learning; Neural networks: ADME; PAMPA; Permeability; QSPR.