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Biosensor-based small molecule fragment screening with biolayer interferometry

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Abstract

Biosensor-based fragment screening is a valuable tool in the drug discovery process. This method is advantageous over many biochemical methods because primary hits can be distinguished from non-specific or non-ideal interactions by examining binding profiles and responses, resulting in reduced false-positive rates. Biolayer interferometry (BLI), a technique that measures changes in an interference pattern generated from visible light reflected from an optical layer and a biolayer containing proteins of interest, is a relatively new method for monitoring small molecule interactions. The BLI format is based on a disposable sensor that is immersed in 96-well or 384-well plates. BLI has been validated for small molecule detection and fragment screening with model systems and well-characterized targets where affinity constants and binding profiles are generally similar to those obtained with surface plasmon resonsance (SPR). Screens with challenging targets involved in protein–protein interactions including BCL-2, JNK1, and eIF4E were performed with a fragment library of 6,500 compounds, and hit rates were compared for these targets. For eIF4E, a protein containing a PPI site and a nucleotide binding site, results from a BLI fragment screen were compared to results obtained in biochemical HTS screens. Overlapping hits were observed for the PPI site, and hits unique to the BLI screen were identified. Hit assessments with SPR and BLI are described.

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Acknowledgments

We thank Huifeng Niu for guidance in eIF4E biology, the Roche Nutley protein group including Linda Reik, Colin Garvie, and Dave Weber for assistance with proteins and protein chemistry, the structure group and chemistry groups including David Fry and Paul Gillespie for assistance with fragment structure, test libraries, and chemistry, Yang Wen for assistance with solubility studies, Steve Ferguson and Samir Serrano for the LC/MS purity studies, and Janet Diratsaoglu, Peggy Borgese, and Sevan Ibabecki for assistance with compounds.

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Authors and Affiliations

  1. Discovery Technologies, Hoffman-La Roche, Nutley, NJ, USA

    Charles A. Wartchow, Frank Podlaski, Shirley Li, Karen Rowan, Xiaolei Zhang, David Mark & Kuo-Sen Huang

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  1. Charles A. Wartchow
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  2. Frank Podlaski
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  3. Shirley Li
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  4. Karen Rowan
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  5. Xiaolei Zhang
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  6. David Mark
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  7. Kuo-Sen Huang
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Correspondence to Charles A. Wartchow.

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Wartchow, C.A., Podlaski, F., Li, S. et al. Biosensor-based small molecule fragment screening with biolayer interferometry. J Comput Aided Mol Des 25, 669–676 (2011). https://doi.org/10.1007/s10822-011-9439-8

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  • DOI: https://doi.org/10.1007/s10822-011-9439-8

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