Detection and Prevention of Aggregation-based False Positives in STD-NMR-based Fragment Screening
Amelia Vom A C , Stephen Headey A , Geqing Wang A , Ben Capuano A , Elizabeth Yuriev A , Martin J. Scanlon A B and Jamie S. Simpson A DA Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Vic. 3052, Australia.
B Australian Research Council Centre of Excellence for Coherent X-ray Science, Monash University, Parkville, Vic. 3052, Australia.
C Current address: Chemical Biology Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Vic. 3052, Australia.
D Corresponding author. Email: jamie.simpson@monash.edu
Australian Journal of Chemistry 66(12) 1518-1524 https://doi.org/10.1071/CH13286
Submitted: 3 June 2013 Accepted: 22 July 2013 Published: 2 September 2013
Abstract
Aggregation of small organic compounds is a problem encountered in a variety of assay screening formats where it often results in detection of false positives. A saturation transfer difference-NMR-detected screen of a commercially available fragment library, followed by biochemical assay, identified several inhibitors of the enzyme ketopantoate reductase. These inhibitors were subsequently revealed to be aggregation-based false positives. Modification of the fragment screen by addition of detergent in the saturation transfer difference-NMR experiments allowed an assay format to be developed that resulted in the identification of genuine hit molecules suitable for further development.
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