| Abstract
| - This study demonstrates a selectivity analysis using the GRID/CPCA strategy on four humancytochrome P450 2C homology models (CYP2C8, 2C9, 2C18, and 2C19). Although the fourenzymes share more than 80% amino acid sequence identity, the substrate specificity differs.To investigate the selectivity of the enzymes and the amino acids that determine the specificityof each CYP2C enzyme, a selectivity analysis was made using GRID/CPCA. In the GRIDcalculations 10 probes were used covering hydrophobic, steric, and hydrogen bond acceptorand donor interactions. The selectivity analysis showed that the most important determinantsof selectivity among the CYP2C models are the geometrical features of the active sites and thehydrophobic interactions. The selectivity analysis singled out CYP2C8 as the most different ofthe four CYP2C enzymes with amino acids with distinct properties in positions 114, 205, and476 (Ser, Phe, and Ile, respectively) compared to the other enzymes. An inverse pharmacophoremodel for CYP2C9 was constructed from the selective regions, and the model agreed with thedocking of diclofenac where the properties of the ligand overlapped with the pharmacophoricpoints in the model.
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