QSAR modeling of in vitro inhibition of cytochrome P450 3A4

We report the QSAR modeling of cytochrome P450 3A4 (CYP3A4) enzyme inhibition using four large data sets of in vitro data. These data sets consist of marketed drugs and drug-like compounds all tested in four assays measuring the inhibition of the metabolism of four different substrates by the CYP3A4 enzyme. The four probe substrates are benzyloxycoumarin, testosterone, benzyloxyresorufin, and midazolam. We first show that using state-of-the-art QSAR modeling approaches applied to only one of these four data sets does not lead to predictive models that would be useful for in silico filtering of chemical libraries. We then present the development and the testing of a multiple pharmacophore hypothesis (MPH) that is formulated as a conceptual extension of the traditional QSAR approach to modeling the promiscuous binding of a large variety of drugs to CYP3A4. In the simplest form, the MPH approach takes advantage of the multiple substrate data sets and identifies the binding of test compounds as either proximal or distal relative to that of a given substrate. Application of the approach to the in silico filtering of test compounds for potential inhibitors of CYP3A4 is also presented. In addition to an improvement in the QSAR modeling for the inhibition of CYP3A4, the results from this modeling approach provide structural insights into the drug-enzyme interactions. The existence of multiple inhibition data sets in the BioPrint database motivates the original development of the concept of a multiple pharmacophore hypothesis and provides a unique opportunity for formulating alternative strategies of QSAR modeling of the inhibition of the in vitro metabolism of CYP3A4.