High confidence predictions of drug-drug interactions: predicting affinities for cytochrome P450 2C9 with multiple computational methods.
Four different models are used to predict whether a compound will bind to 2C9 with a K(i) value of less than 10 microM. 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.
Hudelson
Matthew G
MG
Department of Mathematics, Washington State University, Pullman, WA 99164-3113, USA. mhudelson@wsu.edu
Ketkar
Nikhil S
NS
Holder
Lawrence B
LB
Carlson
Timothy J
TJ
Peng
Chi-Chi
CC
Waldher
Benjamin J
BJ
Jones
Jeffrey P
JP
D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D015195:Drug Design; D004347:Drug Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System