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Structures of endothiapepsin-fragment complexes from crystallographic fragment screening using a novel, diverse and affordable 96-compound fragment library

Huschmann, Franziska U; Linnik, Janina; Sparta, Karine; Ühlein, Monika; Wang, Xiaojie; Metz, Alexander; Schiebel, Johannes; Heine, Andreas; Klebe, Gerhard and Weiss, Manfred S, et al. (2016) In Acta crystallographica. Section F, Structural biology communications 72(Pt 5). p.55-346
Abstract

Crystallographic screening of the binding of small organic compounds (termed fragments) to proteins is increasingly important for medicinal chemistry-oriented drug discovery. To enable such experiments in a widespread manner, an affordable 96-compound library has been assembled for fragment screening in both academia and industry. The library is selected from already existing protein-ligand structures and is characterized by a broad ligand diversity, including buffer ingredients, carbohydrates, nucleotides, amino acids, peptide-like fragments and various drug-like organic compounds. When applied to the model protease endothiapepsin in a crystallographic screening experiment, a hit rate of nearly 10% was obtained. In comparison to other... (More)

Crystallographic screening of the binding of small organic compounds (termed fragments) to proteins is increasingly important for medicinal chemistry-oriented drug discovery. To enable such experiments in a widespread manner, an affordable 96-compound library has been assembled for fragment screening in both academia and industry. The library is selected from already existing protein-ligand structures and is characterized by a broad ligand diversity, including buffer ingredients, carbohydrates, nucleotides, amino acids, peptide-like fragments and various drug-like organic compounds. When applied to the model protease endothiapepsin in a crystallographic screening experiment, a hit rate of nearly 10% was obtained. In comparison to other fragment libraries and considering that no pre-screening was performed, this hit rate is remarkably high. This demonstrates the general suitability of the selected compounds for an initial fragment-screening campaign. The library composition, experimental considerations and time requirements for a complete crystallographic fragment-screening campaign are discussed as well as the nine fully refined obtained endothiapepsin-fragment structures. While most of the fragments bind close to the catalytic centre of endothiapepsin in poses that have been observed previously, two fragments address new sites on the protein surface. ITC measurements show that the fragments bind to endothiapepsin with millimolar affinity.

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type
Contribution to journal
publication status
published
keywords
Fragment screening, Synchrotron radiation, Drug discovery
in
Acta crystallographica. Section F, Structural biology communications
volume
72
issue
Pt 5
pages
10 pages
publisher
Wiley-Blackwell
external identifiers
  • scopus:84969211396
  • wos:000375852400002
ISSN
2053-230X
DOI
10.1107/S2053230X16004623
language
English
LU publication?
no
id
ffcd6f4a-d057-4e7e-9070-2910e942ccd3
date added to LUP
2016-08-05 08:11:47
date last changed
2017-07-02 04:53:11
@article{ffcd6f4a-d057-4e7e-9070-2910e942ccd3,
  abstract     = {<p>Crystallographic screening of the binding of small organic compounds (termed fragments) to proteins is increasingly important for medicinal chemistry-oriented drug discovery. To enable such experiments in a widespread manner, an affordable 96-compound library has been assembled for fragment screening in both academia and industry. The library is selected from already existing protein-ligand structures and is characterized by a broad ligand diversity, including buffer ingredients, carbohydrates, nucleotides, amino acids, peptide-like fragments and various drug-like organic compounds. When applied to the model protease endothiapepsin in a crystallographic screening experiment, a hit rate of nearly 10% was obtained. In comparison to other fragment libraries and considering that no pre-screening was performed, this hit rate is remarkably high. This demonstrates the general suitability of the selected compounds for an initial fragment-screening campaign. The library composition, experimental considerations and time requirements for a complete crystallographic fragment-screening campaign are discussed as well as the nine fully refined obtained endothiapepsin-fragment structures. While most of the fragments bind close to the catalytic centre of endothiapepsin in poses that have been observed previously, two fragments address new sites on the protein surface. ITC measurements show that the fragments bind to endothiapepsin with millimolar affinity.</p>},
  author       = {Huschmann, Franziska U and Linnik, Janina and Sparta, Karine and Ühlein, Monika and Wang, Xiaojie and Metz, Alexander and Schiebel, Johannes and Heine, Andreas and Klebe, Gerhard and Weiss, Manfred S and Mueller, Uwe},
  issn         = {2053-230X},
  keyword      = {Fragment screening,Synchrotron radiation,Drug discovery},
  language     = {eng},
  month        = {05},
  number       = {Pt 5},
  pages        = {55--346},
  publisher    = {Wiley-Blackwell},
  series       = {Acta crystallographica. Section F, Structural biology communications},
  title        = {Structures of endothiapepsin-fragment complexes from crystallographic fragment screening using a novel, diverse and affordable 96-compound fragment library},
  url          = {http://dx.doi.org/10.1107/S2053230X16004623},
  volume       = {72},
  year         = {2016},
}