J Chem Inf Model - Target-specific support vector machine scoring in structure-based virtual screening: computational validation, in vitro testing in kinases, and effects on lung cancer cell proliferation.

Tópicos

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Resumo

We assess the performance of our previously reported structure-based support vector machine target-specific scoring function across 41 targets, 40 among them from the Directory of Useful Decoys (DUD). The area under the curve of receiver operating characteristic plots (ROC-AUC) revealed that scoring with SVM-SP resulted in consistently better enrichment over all target families, outperforming Glide and other scoring functions, most notably among kinases. In addition, SVM-SP performance showed little variation among protein classes, exhibited excellent performance in a test case using a homology model, and in some cases showed high enrichment even with few structures used to train a model. We put SVM-SP to the test by virtual screening 1125 compounds against two kinases, EGFR and CaMKII. Among the top 25 EGFR compounds, three compounds (1-3) inhibited kinase activity in vitro with IC50 of 58, 2, and 10 ?M. In cell cultures, compounds 1-3 inhibited nonsmall cell lung carcinoma (H1299) cancer cell proliferation with similar IC50 values for compound 3. For CaMKII, one compound inhibited kinase activity in a dose-dependent manner among 20 tested with an IC50 of 48 ?M. These results are encouraging given that our in-house library consists of compounds that emerged from virtual screening of other targets with pockets that are different from typical ATP binding sites found in kinases. In light of the importance of kinases in chemical biology, these findings could have implications in future efforts to identify chemical probes of kinases within the human kinome.

Resumo Limpo

assess perform previous report structurebas support vector machin targetspecif score function across target among directori use decoy dud area curv receiv oper characterist plot rocauc reveal score svmsp result consist better enrich target famili outperform glide score function notabl among kinas addit svmsp perform show littl variat among protein class exhibit excel perform test case use homolog model case show high enrich even structur use train model put svmsp test virtual screen compound two kinas egfr camkii among top egfr compound three compound inhibit kinas activ vitro ic m cell cultur compound inhibit nonsmal cell lung carcinoma h cancer cell prolifer similar ic valu compound camkii one compound inhibit kinas activ dosedepend manner among test ic m result encourag given inhous librari consist compound emerg virtual screen target pocket differ typic atp bind site found kinas light import kinas chemic biolog find implic futur effort identifi chemic probe kinas within human kinom

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