Kinase-Targeted Library Design through the Application of the PharmPrint Methodology
| Autor: | Michael J. Reno, Eugene L. Stewart, Felix Deanda, David H. Drewry |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Library design
Quantitative structure–activity relationship Computer science General Chemical Engineering Drug Evaluation Preclinical Quantitative Structure-Activity Relationship Protein Serine-Threonine Kinases Library and Information Sciences computer.software_genre Rho-Associated Kinases User-Computer Interface Aurora Kinases Drug Discovery Combinatorial Chemistry Techniques Computer Simulation Screening tool Databases Protein Protein Kinase Inhibitors rho-Associated Kinases Virtual screening Drug discovery General Chemistry Computer Science Applications Hit rate Data mining Proto-Oncogene Proteins c-akt computer |
| Zdroj: | Journal of Chemical Information and Modeling. 48:2395-2403 |
| ISSN: | 1549-960X 1549-9596 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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