Modelling of intrinsic membrane permeability of drug molecules by explainable ML-based q-RASPR approach towards better pharmacokinetics and toxicokinetics properties

Drug discovery’s success lies in potent inhibition against a target and optimum pharmacokinetic and toxicokinetic properties of drug molecules. Membrane permeability is a crucial factor in determining the absorption, distribution, metabolism, and excretion of drug molecules, thereby determining the pharmacokinetic and toxicokinetic properties important for drug development. Intrinsic permeability (P₀) is more crucial than apparent permeability (Papp) in assessing the transport of drug molecules across a membrane. It gives more consistent results due to its non-dependency on external/site-specific factors. In the present work, our focus is on the construction of a machine learning (ML)-based quantitative read-across structure–property relationship (q-RASPR) model of intrinsic permeability of drug molecules by utilizing both linear and non-linear algorithms. The Support Vector Regression (SVR) q-RASPR model was found to be the best model having superior predictive ability (<i>Q</i>²_F1 = 0.788, <i>Q</i>²_F2 = 0.785, <i>MAE</i>_test = 0.637). The contribution of important descriptors in the final model is explained to get a mechanistic interpretation of intrinsic permeability. Overall, the present study unveils the application of the q-RASPR framework for significant improvement of the external predictivity of the traditional QSPR model in the case of intrinsic permeability to get a better assessment of the total permeability of drug molecules.