Search

CYP2C9 is a significant P450 protein responsible for drug metabolism. With the increased use of heterocyclic compounds in drug design, a rapid and efficient predrug screening of these potential type II binding compounds is essential to avoid adverse drug reactions. To understand binding modes, we use quinoline-4-carboxamide analogues to study the factors that determine the structure−activity relationships. The results of this study suggest that the more accessible pyridine with the nitrogen para to the linkage can coordinate directly with the ferric heme iron, but this is not seen for the meta or ortho isomers. The π−cation interaction of the naphthalene moiety and Arg 108 residue may also assist in stabilizing substrate binding within the active-site cavity. The type II substrate binding affinity is determined by the combination of steric, electrostatic, and hydrophobicity factors; meanwhile, it is enhanced by the strength of lone pair electrons coordination with the heme iron. [ABSTRACT FROM AUTHOR]

Four different models are used to predict whether a compound will bind to 2C9 with a K ivalue of less than 10 µM. A training set of 276 compounds and a diverse validation set of 50 compounds were used to build and assess each model. The modeling methods are chosen to exploit the differences in how training sets are used to develop the predictive models. Two of the four methods develop partitioning trees based on global descriptions of structure using nine descriptors. A third method uses the same descriptors to develop local descriptions that relate activity to structures with similar descriptor characteristics. The fourth method uses a graph-theoretic approach to predict activity based on molecular structure. When all of these methods agree, the predictive accuracy is 94%. An external validation set of 11 compounds gives a predictive accuracy of 91% when all methods agree. [ABSTRACT FROM AUTHOR]