Target Immobilization as a Strategy for NMR-Based Fragment Screening: Comparison of TINS, STD, and SPR for Fragment Hit Identification

M. Kobayashi, K. Retra, F. Figaroa, J.G. Hollander, E. Ab, R.J. Heetebrij, H. Irth, G. Siegal

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Fragment-based drug discovery (FBDD) has become a widely accepted tool that is complementary to high-throughput screening (HTS) in developing small-molecule inhibitors of pharmaceutical targets. Because a fragment campaign can only be as successful as the hit matter found, it is critical that the first stage of the process be optimized. Here the authors compare the 3 most commonly used methods for hit discovery in FBDD: high concentration screening (HCS), solution ligand-observed nuclear magnetic resonance (NMR), and surface plasmon resonance (SPR). They selected the commonly used saturation transfer difference (STD) NMR spectroscopy and the proprietary target immobilized NMR screening (TINS) as representative of the array of possible NMR methods. Using a target typical of FBDD campaigns, the authors find that HCS and TINS are the most sensitive to weak interactions. They also find a good correlation between TINS and STD for tighter binding ligands, but the ability of STD to detect ligands with affinity weaker than 1 mM K
Original languageEnglish
Pages (from-to)978-989
JournalJournal of Biomolecular Screening
Volume15
Issue number8
DOIs
Publication statusPublished - 2010

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