PMID: 19929836Nov 26, 2009Paper

Target immobilization and NMR screening of fragments in early drug discovery

Current Topics in Medicinal Chemistry
Gregg Siegal, Johan G Hollander

Abstract

Using localized NMR spectroscopy on immobilized targets provides us with a method to simultaneously assess binding of small molecules to two different samples. This Target Immobilized NMR Screening (TINS) has a number of advantages, not least is the requirement for minimal quantities of non-isotopically labeled protein and the applicability to insoluble or unstable targets. The technique is sensitive to binding with K(D) values in the range of 100 nM to 20 mM, while careful selection of the reference protein reduces the number of false positive hits. This combination ensures a maximal number of valid hits from which to select starting points for hit elaboration projects. Hits can be prioritized using biological assays when appropriate, as well as an array of biophysical techniques. So far a variety of soluble proteins, including kinases, GTPases, viral targets and proteases, as well as a membrane protein, have been successfully screened against our fragment library. Here we illustrate our experiences with a number of examples which emphasize the usefulness of the method in selecting and prioritizing fragment hits for elaboration towards leads.

Citations

Aug 3, 2010·Neuropharmacology·Roderick E Hubbard
Jan 26, 2012·Journal of Medicinal Chemistry·Rongshi LiSaid M Sebti
Aug 2, 2017·The Journal of Physical Chemistry. B·Linda CerofoliniClaudio Luchinat

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