title: Kinase-targeted library design through the application of the PharmPrint methodology.
abstract: The PharmPrint methodology, as modified and implemented by Deanda and Stewart, was prospectively evaluated for use as a virtual high-throughput screening tool by applying it to the design of target-focused arrays. To this end, PharmPrint quantitative structure-activity relationship (QSAR) models for the prediction of AKT1, Aurora-A, and ROCK1 inhibition were constructed and used to virtually screen two large combinatorial libraries. Based on predicted activities, an Aurora-A targeted array and a ROCK1 targeted array were designed and synthesized. One control group per designed array was also synthesized to assess the enrichment levels achieved by the QSAR models. For the Aurora-A targeted array, the hit rate, against the intended target, was 42.9%, whereas that of the control group was 0%. Thus, the enrichment level achieved by the Aurora-A QSAR model was incalculable. For the ROCK1 targeted array, the hit rate against the intended target was 30.6%, whereas that of the control group was 5.10%, making the enrichment level achieved by the ROCK1 QSAR model 6-fold above control. Clearly, these results support the use of the PharmPrint methodology as a virtual screening tool for the design of kinase-targeted arrays.
authors.affiliation: GlaxoSmithKline, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. felix.g.deanda@gsk.com
authors.forename: Felix
authors.initials: F
authors.lastname: Deanda
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Stewart
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reno
authors.forename: David H
authors.initials: DH
authors.lastname: Drewry
mesh_terms: D064127:Aurora Kinases; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D030562:Databases, Protein; D055808:Drug Discovery / Q000706:statistics & numerical data; D004353:Drug Evaluation, Preclinical / Q000706:statistics & numerical data*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D021281:Quantitative Structure-Activity Relationship; D014584:User-Computer Interface; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases