Cytochrome P450 3A4Modeling small-molecule binding to Cytochrome P450 3A4.
Metabolic transformation of drugs may jeopardize their beneficial properties, reduce the bioavailability and lead to undesired, e.g. toxic, effects. The prediction of metabolic reactions paths for molecules of biomedical interest is therefore of considerable importance in the drug-development process. The superfamily of cytochrome P450 enzymes plays a major role in the biotransformation of xenobiotics either by inactivating or activating a chemical functionality. CYPs enhance solubilization and elimination of such compounds but are also responsible for some aspects of drug toxicity — either by processing benign drugs to toxic metabolites or by inhibition of specific CYP isoenzymes by such entities.
Stereo representation of Amiodarone bound to the CYP3A4 binding-site surrogate as generated by Raptor 2.0
Based on the 2.0 Å resolution structure of CP450 3A4 (PDB code = 1TQN), we have docked a variety of medium-size ligands and sampled all possible binding modes by means of a Monte-Carlo/Metropolis search protocol as implemented in the Yeti software. Those orientations were then composed into a 4D data set and quantified using multi-dimensional QSAR (Quasar and Raptor software).
Comparison of experimental and predicted IC50 values for Cytochrome P450 3A4
(training set = dark green, test set = red; treshold compounds light green = training, orange = test)