Virtual target screening: Validation using kinase inhibitors

Daniel N. Santiago, Yuri Pevzner, Ashley A. Durand, Minhphuong Tran, Rachel R. Scheerer, Kenyon Daniel, Shen Shu Sung, H. Lee Woodcock, Wayne C. Guida, Wesley H. Brooks

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Computational methods involving virtual screening could potentially be employed to discover new biomolecular targets for an individual molecule of interest (MOI). However, existing scoring functions may not accurately differentiate proteins to which the MOI binds from a larger set of macromolecules in a protein structural database. An MOI will most likely have varying degrees of predicted binding affinities to many protein targets. However, correctly interpreting a docking score as a hit for the MOI docked to any individual protein can be problematic. In our method, which we term "Virtual Target Screening (VTS)", a set of small drug-like molecules are docked against each structure in the protein library to produce benchmark statistics. This calibration provides a reference for each protein so that hits can be identified for an MOI. VTS can then be used as tool for: drug repositioning (repurposing), specificity and toxicity testing, identifying potential metabolites, probing protein structures for allosteric sites, and testing focused libraries (collection of MOIs with similar chemotypes) for selectivity. To validate our VTS method, twenty kinase inhibitors were docked to a collection of calibrated protein structures. Here, we report our results where VTS predicted protein kinases as hits in preference to other proteins in our database. Concurrently, a graphical interface for VTS was developed.

Original languageEnglish (US)
Pages (from-to)2192-2203
Number of pages12
JournalJournal of Chemical Information and Modeling
Volume52
Issue number8
DOIs
StatePublished - Aug 27 2012

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

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    Santiago, D. N., Pevzner, Y., Durand, A. A., Tran, M., Scheerer, R. R., Daniel, K., Sung, S. S., Lee Woodcock, H., Guida, W. C., & Brooks, W. H. (2012). Virtual target screening: Validation using kinase inhibitors. Journal of Chemical Information and Modeling, 52(8), 2192-2203. https://doi.org/10.1021/ci300073m