title: Calculation and application of activity discriminants in lead optimization.
abstract: 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.
authors.affiliation: Department of Chemistry, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19850, USA. Xincai.Luo@astrazeneca.com
authors.forename: Xincai
authors.initials: X
authors.lastname: Luo
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Krumrine
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Shenvi
authors.forename: M Edward
authors.initials: ME
authors.lastname: Pierson
authors.forename: Peter R
authors.initials: PR
authors.lastname: Bernstein
mesh_terms: D001681:Biological Assay / Q000379:methods*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004364:Pharmaceutical Preparations