Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery.

ABSTRACT: In fragment-based drug discovery, the weak affinities exhibited by fragments pose significant challenges for screening. Biophysical techniques are used to address this challenge, but there is no clear consensus on which cascade of methods is best suited to identify fragment hits that ultimately translate into bound X-ray structures and provide bona fide starting points for synthesis. We have benchmarked an integrated biophysical approach for fragment screening and validation against Mycobacterium tuberculosis pantothenate synthetase. A primary screen of 1,250 fragments library was performed by thermal shift, followed by secondary screen using one-dimensional NMR spectroscopy (water ligand observed gradient spectroscopy and saturation transfer difference binding experiments) and ultimate hi

SUBMITTER: Silvestre HL 

PROVIDER: S-EPMC3740835 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature