Predict of metabolic stability of xenobiotics by the PASS and GUSAR programs

Abstract

Metabolic stability refers to the susceptibility of compounds to the biotransformation; it is characterized by such pharmacokinetic parameters as half-life (T1/2) and clearance (CL). Generally, these parameters are estimated by in vitro assays, which are based on cells or subcellular fractions (mainly liver microsomal enzymes) and serve as models of the processes occurring in living organisms. Data obtained from the experiments are used to build QSAR (Quantitative Structure-Activity Relationship) models. More than 8000 compounds with known CL and/or T1/2 values obtained in vitro using human liver microsomes were selected from the freely available ChEMBL v.27 database. GUSAR (General Unrestricted Structure-Activity Relationships) and PASS (Prediction of Activity Spectra for Substances) softwares were used to make quantitative and classification models. The quality of the models was evaluated using 5-fold cross-validation. Compounds were subdivided into "stable" and "unstable" by means of the following threshold parameters: T1/2 = 30 minutes, CL = 20 ml/min/kg. The accuracy of the models ranged from 0.5 (calculated in 5-fold CV on the test set for the half-life prediction quantitative model) to 0.96 (calculated in 5-fold CV on the test set for the clearance prediction classification model).