Computational models for identifying potential P-glycoprotein substrates and inhibitors.

Multidrug resistance mediated by ATP binding cassette (ABC) transporters such as P-glycoprotein (P-gp) represents a serious problem for the development of effective anticancer drugs. In addition, P-gp has been shown to reduce oral absorption, modulate hepatic, renal, or intestinal elimination, and restrict blood-brain barrier penetration of several drugs. Consequently, there is a great interest in anticipating whether drug candidates are P-gp substrates or inhibitors. In this respect, two different computational models have been developed. A method for discriminating P-gp substrates and nonsubstrates has been set up based on calculated molecular descriptors and multivariate analysis using a training set of 53 diverse drugs. These compounds were previously classified as P-gp substrates or nonsubstrates on the basis of the efflux ratio from Caco-2 permeability measurements. The program Volsurf was used to compute the compounds' molecular descriptors. The descriptors were correlated to the experimental classes using partial least squares discriminant analysis (PLSD). The model was able to predict correctly the behavior of 72% of an external set of 272 proprietary compounds. Thirty of the 53 previously mentioned drugs were also evaluated for P-gp inhibition using a calcein-AM (CAM) assay. On the basis of these additional P-gp functional data, a PLSD analysis using GRIND-pharmacophore-based descriptors was performed to model P-gp substrates having poor or no inhibitory activity versus inhibitors having no evidence of significant transport. The model was able to discriminate between 69 substrates and 56 inhibitors taken from the literature with an average accuracy of 82%. The model allowed also the identification of some key molecular features that differentiate a substrate from an inhibitor, which should be taken into consideration in the design of new candidate drugs. These two models can be implemented in a virtual screening funnel.