Six Biophysical Screening Methods Miss a Large Proportion of Crystallographically Discovered Fragment Hits: A Case Study

Johannes Schiebel, Nedyalka Radeva, Stefan G Krimmer, Xiaojie Wang, Martin Stieler, Frederik R Ehrmann, Kan Fu, Alexander Metz, Franziska U Huschmann, Manfred S Weiss, Uwe Mueller, Andreas Heine, Gerhard Klebe

Research output: Contribution to journalArticlepeer-review

Abstract

Fragment-based lead discovery (FBLD) has become a pillar in drug development. Typical applications of this method comprise at least two biophysical screens as prefilter and a follow-up crystallographic experiment on a subset of fragments. Clearly, structural information is pivotal in FBLD, but a key question is whether such a screening cascade strategy will retrieve the majority of fragment-bound structures. We therefore set out to screen 361 fragments for binding to endothiapepsin, a representative of the challenging group of aspartic proteases, employing six screening techniques and crystallography in parallel. Crystallography resulted in the very high number of 71 structures. Yet alarmingly, 44% of these hits were not detected by any biophysical screening approach. Moreover, any screening cascade, building on the results from two or more screening methods, would have failed to predict at least 73% of these hits. We thus conclude that, at least in the present case, the frequently applied biophysical prescreening filters deteriorate the number of possible X-ray hits while only the immediate use of crystallography enables exhaustive retrieval of a maximum of fragment structures, which represent a rich source guiding hit-to-lead-to-drug evolution.

Original languageEnglish
Pages (from-to)1693-701
Number of pages9
JournalACS Chemical Biology
Volume11
Issue number6
DOIs
Publication statusPublished - 2016 Jun 17
Externally publishedYes

Subject classification (UKÄ)

  • Structural Biology

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