Prediction of P-glycoprotein inhibitors with machine learning classification models and 3D-RISM-KH theory based solvation energy descriptors.

Development of novel in silico methods for questing novel PgP inhibitors is crucial for the reversal of multi-drug resistance in cancer therapy. Here, we report machine learning based binary classification schemes to identify the PgP inhibitors from non-inhibitors using molecular solvation theory with excellent accuracy and precision. The excess chemical potential and partial molar volume in various solvents are calculated for PgP± (PgP inhibitors and non-inhibitors) compounds with the statistical-mechanical based three-dimensional reference interaction site model with the Kovalenko-Hirata closure approximation (3D-RISM-KH molecular theory of solvation). The statistical importance analysis of descriptors identified the 3D-RISM-KH based descriptors as top molecular descriptors for classification. Among the constructed classification models, the support vector machine predicted the test set of Pgp± compounds with highest accuracy and precision of ~ 97% for test set. The validation of models confirms the robustness of state-of-the-art molecular solvation theory based descriptors in identification of the Pgp± compounds.