Projects

Cytochrome P450 2A13

Modeling small-molecule binding to Cytochrome P450 2A13.

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.

Close-up of the indole binding to the enzyme.

Based on the 2.35 Å resolution structure of CP450 2A13 (PDB code = 2P85), we have docked 24 different compounds 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 the 6D-QSAR software Quasar.

Comparison of experimental and predicted IC50 values for Cytochrome P450 2A13
(training set = black, test set = red)

Reference: Publication pending.