Multivariate modeling of cytochrome P450 3A4 inhibition

In the early phases of current pharmaceutical research projects, huge numbers of compounds are tested on their biological activity with respect to a certain target by experimental or virtual screening campaigns. To reduce the attrition rate in later stages of a project, other relevant properties such as physicochemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) properties should be assessed as early as possible in lead discovery and optimization. The present study describes the development of in silico models to predict the inhibition of human cytochrome P450 3A4 (CYP3A4) from calculated molecular descriptors. The models were trained and validated using a set of 967 structural diverse drug-like research compounds with an experimentally determined CYP3A4 inhibition potency (IC50 value) which was carefully split into a training and a test set. For classification models, the data sets were further subdivided into strong, medium, and weak inhibitors. Different descriptor sets were used to cover various aspects of molecular properties, including properties derived from the 2D structure, the interaction of the molecule with its environment, and properties derived from quantum-mechanical calculations. The descriptors were related to the CYP3A4 inhibition potency by multivariate data analysis methods such as partial least-squares projection to latent structures (PLS), PLS discriminant analysis (PLS-DA), and soft independent class modeling (SIMCA). The squared correlation between experimental and predicted IC50 values of the previously unseen test set compounds was Qext2=0.6 for the best PLS models, corresponding to a root mean squared error (RMSE) of RMSE=0.45 (logarithm of IC50). The best PLS-DA models were able to correctly classify more than 60% of the test set compounds, whereas almost no strong inhibitors were wrongly classified as weak inhibitors and vice versa. Furthermore, relevant molecular properties were identified which are closely related to the CYP3A4 inhibition potency of a compound. The results presented here are very encouraging since our models could, for instance, serve to flag problematic compounds or to guide further synthesis efforts.