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

Schiebel, Johannes; Radeva, Nedyalka; Krimmer, Stefan G; Wang, Xiaojie; Stieler, Martin; Ehrmann, Frederik R; Fu, Kan; Metz, Alexander; Huschmann, Franziska U and Weiss, Manfred S, et al. (2016) In ACS Chemical Biology 11(6). p.701-1693
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... (More)

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.

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ACS Chemical Biology
volume
11
issue
6
pages
9 pages
publisher
The American Chemical Society
external identifiers
  • Scopus:84975230932
ISSN
1554-8937
DOI
10.1021/acschembio.5b01034
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English
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no
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cd22765c-c4e8-4ffc-94b7-53ba159f0636
date added to LUP
2016-08-05 08:15:37
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2016-11-27 04:42:01
@misc{cd22765c-c4e8-4ffc-94b7-53ba159f0636,
  abstract     = {<p>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.</p>},
  author       = {Schiebel, Johannes and Radeva, Nedyalka and Krimmer, Stefan G and Wang, Xiaojie and Stieler, Martin and Ehrmann, Frederik R and Fu, Kan and Metz, Alexander and Huschmann, Franziska U and Weiss, Manfred S and Mueller, Uwe and Heine, Andreas and Klebe, Gerhard},
  issn         = {1554-8937},
  language     = {eng},
  month        = {06},
  number       = {6},
  pages        = {701--1693},
  publisher    = {ARRAY(0xac9a4f8)},
  series       = {ACS Chemical Biology},
  title        = {Six Biophysical Screening Methods Miss a Large Proportion of Crystallographically Discovered Fragment Hits : A Case Study},
  url          = {http://dx.doi.org/10.1021/acschembio.5b01034},
  volume       = {11},
  year         = {2016},
}