3D-QSAR methods on the basis of ligand-receptor complexes. Application of COMBINE and GRID/GOLPE methodologies to a series of CYP1A2 ligands

Many heterocyclic amines (HCA) present in cooked food exert a genotoxic act ivity when they are metabolised (N-oxidated) by the human cytochrome P450 1 A2 (CYP1A2h). In order to rationalize the observed differences in activity of this enzyme on a series of 12 HCA, 3D-QSAR methods were applied on the b asis of models of HCA-CYP1A2h complexes. The CYP1A2h enzyme model has been previously reported and was built by homology modeling based on cytochrome P450 BM3. The complexes were automatically generated applying the AUTODOCK software and refined using AMBER. A COMBINE analysis on the complexes ident ified the most important enzyme-ligand interactions that account for the di fferences in activity within the series. A GRID/GOLPE analysis was then per formed on just the ligands, in the conformations and orientations found in the modeled complexes. The results from both methods were concordant and co nfirmed the advantages of incorporating structural information from series of ligand-receptor complexes into 3D-QSAR methodologies.