Calculation and application of activity discriminants in lead optimization
We present a technique for computing activity discriminants of in vitro (pharmacological, DMPK, and safety) assays and the application to the prediction of in vitro activities of proposed synthetic targets during the lead optimization phase of drug discovery projects. This technique emulates how medicinal chemists perform SAR analysis and activity prediction. The activity discriminants that are functions of 6 commonly used medicinal chemistry descriptors can be interpreted easily by medicinal chemists. Further, visualization with Spotfire allows medicinal chemists to analyze how the query molecule is related to compounds tested previously, and to evaluate easily the relevance of the activity discriminants to the activities of the query molecule. Validation with all compounds synthesized and tested in AstraZeneca Wilmington since 2006 demonstrates that this approach is useful for prioritizing new synthetic targets for synthesis.
lda linear discriminant analysis ld linear discriminant mw molecular weight clogp calculated water and alcohol partition coefficient tpsa topological polar surface area nhd number of hydrogen bond donors nha number of hydrogen bond acceptors nrb number of rotatable bonds hclint human microsome metabolism intrinsic clearance herg human ether-a-go-go related gene dmpk drug metabolism and pharmacokinetics qsar quantitative structureactivity relationship 2d two-dimensional 3d three-dimensional pe percent effect