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Current Topics in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Fragment Based Drug Discovery Using Fluorescence Correlation Spectroscopy Techniques: Challenges and Solutions

Author(s): T. Hesterkamp, J. Barker, A. Davenport and M. Whittaker

Volume 7, Issue 16, 2007

Page: [1582 - 1591] Pages: 10

DOI: 10.2174/156802607782341064

Price: $65

Abstract

Novel starting points for medicinal chemistry programmes can be effectively identified by screening libraries of fragment molecules in biochemical assays at high concentration. The key to success with this approach is the combination of a high quality fragment library with sensitive biochemical screening methods. There are an increasing number of literature reports where weakly active fragment molecules have been identified by high concentration biochemical assays. We have successfully demonstrated the use of high concentration screening of fragments, using a portfolio of single-molecule Fluorescence Correlation Spectroscopy (FCS+plus) detection techniques to ensure the highest reproducibility and sensitivity, and have determined the binding mode of active fragments to target proteins by X-ray crystallography. Further biophysical detection methods are reviewed for their applicability to studies of fragment binding.

Keywords: Fragments, screening, X-ray crystallography, biochemical assay, high-concentration, single-molecule spectroscopy, haematopoietic prostaglandin D2 synthase


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