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Active Site Mapping of an Aspartic Protease by Multiple Fragment Crystal Structures : Versatile Warheads to Address a Catalytic Dyad

Radeva, Nedyalka; Schiebel, Johannes; Wang, Xiaojie; Krimmer, Stefan G.; Fu, Kan; Stieler, Martin; Ehrmann, Frederik R.; Metz, Alexander; Rickmeyer, Thomas and Betz, Michael, et al. (2016) In Journal of Medicinal Chemistry 59(21). p.9743-9759
Abstract

Crystallography is frequently used as follow-up method to validate hits identified by biophysical screening cascades. The capacity of crystallography to directly screen fragment libraries is often underestimated, due to its supposed low-throughput and need for high-quality crystals. We applied crystallographic fragment screening to map the protein-binding site of the aspartic protease endothiapepsin by individual soaking experiments. Here, we report on 41 fragments binding to the catalytic dyad and adjacent specificity pockets. The analysis identifies already known warheads but also reveals hydrazide, pyrazole, or carboxylic acid fragments as novel functional groups binding to the dyad. A remarkable swapping of the S1 and S1′ pocket... (More)

Crystallography is frequently used as follow-up method to validate hits identified by biophysical screening cascades. The capacity of crystallography to directly screen fragment libraries is often underestimated, due to its supposed low-throughput and need for high-quality crystals. We applied crystallographic fragment screening to map the protein-binding site of the aspartic protease endothiapepsin by individual soaking experiments. Here, we report on 41 fragments binding to the catalytic dyad and adjacent specificity pockets. The analysis identifies already known warheads but also reveals hydrazide, pyrazole, or carboxylic acid fragments as novel functional groups binding to the dyad. A remarkable swapping of the S1 and S1′ pocket between structurally related fragments is explained by either steric demand, required displacement of a well-bound water molecule, or changes of trigonal-planar to tetrahedral geometry of an oxygen functional group in a side chain. Some warheads simultaneously occupying both S1 and S1′ are promising starting points for fragment-growing strategies.

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Journal of Medicinal Chemistry
volume
59
issue
21
pages
17 pages
publisher
American Chemical Society (ACS)
external identifiers
  • scopus:84994908405
  • wos:000387737600009
ISSN
0022-2623
DOI
10.1021/acs.jmedchem.6b01195
language
English
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yes
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a24dd668-42dd-4602-ac8c-bdacb531b07b
date added to LUP
2016-11-28 14:42:14
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2017-07-02 04:56:36
@article{a24dd668-42dd-4602-ac8c-bdacb531b07b,
  abstract     = {<p>Crystallography is frequently used as follow-up method to validate hits identified by biophysical screening cascades. The capacity of crystallography to directly screen fragment libraries is often underestimated, due to its supposed low-throughput and need for high-quality crystals. We applied crystallographic fragment screening to map the protein-binding site of the aspartic protease endothiapepsin by individual soaking experiments. Here, we report on 41 fragments binding to the catalytic dyad and adjacent specificity pockets. The analysis identifies already known warheads but also reveals hydrazide, pyrazole, or carboxylic acid fragments as novel functional groups binding to the dyad. A remarkable swapping of the S1 and S1′ pocket between structurally related fragments is explained by either steric demand, required displacement of a well-bound water molecule, or changes of trigonal-planar to tetrahedral geometry of an oxygen functional group in a side chain. Some warheads simultaneously occupying both S1 and S1′ are promising starting points for fragment-growing strategies.</p>},
  author       = {Radeva, Nedyalka and Schiebel, Johannes and Wang, Xiaojie and Krimmer, Stefan G. and Fu, Kan and Stieler, Martin and Ehrmann, Frederik R. and Metz, Alexander and Rickmeyer, Thomas and Betz, Michael and Winquist, Johan and Park, Ah Young and Huschmann, Franziska U. and Weiss, Manfred S. and Müller, Uwe and Heine, Andreas and Klebe, Gerhard},
  issn         = {0022-2623},
  language     = {eng},
  month        = {11},
  number       = {21},
  pages        = {9743--9759},
  publisher    = {American Chemical Society (ACS)},
  series       = {Journal of Medicinal Chemistry},
  title        = {Active Site Mapping of an Aspartic Protease by Multiple Fragment Crystal Structures : Versatile Warheads to Address a Catalytic Dyad},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.6b01195},
  volume       = {59},
  year         = {2016},
}