Analysis of selective regions in the active sites of human cytochromes P450, 2CS, 2C9, 2C18, and 2C19 homology models using GRID/CPCA

This study demonstrates a selectivity analysis using the GRID/CPCA strategy on four human cytochrome P450 2C homology models (CYP2C8, 2C9, 2C18, and 2 C19). Although the four enzymes share more than 80% amino acid sequence ide ntity, the substrate specificity differs. To investigate the selectivity of the enzymes and the amino acids that determine the specificity of each CYP 2C enzyme, a selectivity analysis was made using GRID/CPCA. In the GRID cal culations 10 probes were used covering hydrophobic, steric, and hydrogen bo nd acceptor and donor interactions. The selectivity analysis showed that th e most important determinants of selectivity among the CYP2C models are the geometrical features of the active sites and the hydrophobic interactions. The selectivity analysis singled out CYP2C8 as the most different of the f our CYP2C enzymes with amino acids with distinct properties in positions 11 4, 205, and 476 (Ser, Phe, and Ile, respectively) compared to the other enz ymes. An inverse pharmacophore model for CYP2C9 was constructed from the se lective regions, and the model agreed with the docking of diclofenac where the properties of the ligand overlapped with the pharmacophoric points in t he model.