A fast virtual screening filter for cytochrome P450 3A4 inhibition liability of compound libraries

Current virtual screening applications focus not only on biological activity, but also on additional relevant properties of drug candidates, like absorption, distribution, metabolism, and excretion (ADME). In first-pass virtual screening, these prediction systems must be very fast because typically several millions of compounds must be processed. We have developed a linear PLS-based prediction system for binary classification of drug-drug interaction liability caused by cytochrome P450 3A4 inhibition. The system was trained using IC 5 0 values of 311 carefully selected molecules out of a raw data set containing 1152 compounds. It correctly predicts 95% of the training data and 90% of a semi-independent validation data set. The PLS model was calculated from 333 descriptors encoding a molecule. It outperforms an approach utilizing a three layered feed-forward artificial neural network architecture. The average calculation time required for a prediction is less than 0.3 seconds per molecule on a single microprocessor.