Cambridge MedChem Consulting

Cytochrome 1A2 inhibition

Whilst cytochrome 1A2 has a relatively minor role in the metabolism of xenobiotics (8% of drugs) some of the more potent CYP1A2 inhibitors include cimetidine, ciprofloxacin, enoxacin, and fluvoxamine.


CYP1A2 Inhibition Data from ChEMBL

ChEMBL is a database of bioactive drug-like small molecules, it contains 2-D structures, calculated properties (e.g. logP, Molecular Weight, Lipinski Parameters, etc.) and abstracted bioactivities (e.g. binding constants, pharmacology and ADMET data). Currently it contains data for 1,359,508 molecules and 9,414 different targets. ChEMBL contains data for CYP1A2 inhibitors, I downloaded all the IC50 data and imported it into Vortex, I then deleted those results that the ChEMBL team had flagged as potentially unreliable. Then I calculated a number of physicochemical properties using a variety of scripts.

Looking at the scatter plot below it appears that LogP has little impact on inhibition, however most of the most potent inhibitors are neutral (yellow). Inspection of the most potent inhibitors reveals they all contain aromatic rings.


Matched Pair Analysis

Using Vortex to conduct a matched pair analysis helps to identify small changes that have a significant influence on the CYP1A2 inhibition. As might be expected several of the more potent inhibitors have a heterocycle that can coordinate to the iron in the haem ring of the cytochrome. The matched pair analysis identifies a number of examples where modification of the heterocycle has a significant effect on inhibition. Either by sterically encumbering the nitrogen proposed to coordinate to the iron, or by reducing the electron density on the nitrogen. An alternative approach has been to replace a pyridine with the bioisosteric fluoro or chloro phenyl. These results mirror those described in more detail on the CYP3A4 inhibitors and CYP2D6 inhibitors pages.


Whilst a number of the more potent inhibitors contain a heterocycle that can coordinate to the iron there is a group of neutral fact aromatic molecules, in these cases substitution on the aromatic ring can have profound effects.


See Also

Last Updated11 November 2018