Kinase-targeted library design through the application of the PharmPrint methodology

J Chem Inf Model. 2008 Dec;48(12):2395-403. doi: 10.1021/ci800276t.

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.

Publication types

  • Evaluation Study

MeSH terms

  • Aurora Kinases
  • Combinatorial Chemistry Techniques
  • Computer Simulation
  • Databases, Protein
  • Drug Discovery / statistics & numerical data
  • Drug Evaluation, Preclinical / statistics & numerical data*
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Quantitative Structure-Activity Relationship
  • User-Computer Interface
  • rho-Associated Kinases / antagonists & inhibitors

Substances

  • Protein Kinase Inhibitors
  • Aurora Kinases
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • rho-Associated Kinases