Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

F2X-Universal and F2X-Entry : Structurally Diverse Compound Libraries for Crystallographic Fragment Screening

Wollenhaupt, Jan ; Metz, Alexander ; Barthel, Tatjana ; Lima, Gustavo M.A. LU orcid ; Heine, Andreas ; Mueller, Uwe LU ; Klebe, Gerhard and Weiss, Manfred S. (2020) In Structure 28. p.694-706
Abstract

Crystallographic fragment screening (CFS) provides excellent starting points for projects concerned with drug discovery or biochemical tool compound development. One of the fundamental prerequisites for effective CFS is the availability of a versatile fragment library. Here, we report on the assembly of the 1,103-compound F2X-Universal Library and its 96-compound sub-selection, the F2X-Entry Screen. Both represent the available fragment chemistry and are highly diverse in terms of their 3D-pharmacophore variations. Validation of the F2X-Entry Screen in CFS campaigns using endothiapepsin and the Aar2/RNaseH complex yielded hit rates of 30% and 21%, respectively, and revealed versatile binding sites. Dry presentation of the libraries... (More)

Crystallographic fragment screening (CFS) provides excellent starting points for projects concerned with drug discovery or biochemical tool compound development. One of the fundamental prerequisites for effective CFS is the availability of a versatile fragment library. Here, we report on the assembly of the 1,103-compound F2X-Universal Library and its 96-compound sub-selection, the F2X-Entry Screen. Both represent the available fragment chemistry and are highly diverse in terms of their 3D-pharmacophore variations. Validation of the F2X-Entry Screen in CFS campaigns using endothiapepsin and the Aar2/RNaseH complex yielded hit rates of 30% and 21%, respectively, and revealed versatile binding sites. Dry presentation of the libraries allows CFS campaigns to be carried out with or without the co-solvent DMSO present. Most of the hits in our validation campaigns could be reproduced also in the absence of DMSO. Consequently, CFS can be carried out more efficiently and for a wider range of conditions and targets.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aar2, compound library, drug design, endothiapepsin, FBDD, fragment screening, protein-protein complex, Prp8 RNaseH, X-ray crystallography
in
Structure
volume
28
pages
694 - 706
publisher
Cell Press
external identifiers
  • scopus:85085291329
  • pmid:32413289
ISSN
0969-2126
DOI
10.1016/j.str.2020.04.019
language
English
LU publication?
yes
id
1f89c5e1-dba8-4b84-a8ee-02be2386efb7
date added to LUP
2020-06-15 13:07:39
date last changed
2024-05-30 16:52:37
@article{1f89c5e1-dba8-4b84-a8ee-02be2386efb7,
  abstract     = {{<p>Crystallographic fragment screening (CFS) provides excellent starting points for projects concerned with drug discovery or biochemical tool compound development. One of the fundamental prerequisites for effective CFS is the availability of a versatile fragment library. Here, we report on the assembly of the 1,103-compound F2X-Universal Library and its 96-compound sub-selection, the F2X-Entry Screen. Both represent the available fragment chemistry and are highly diverse in terms of their 3D-pharmacophore variations. Validation of the F2X-Entry Screen in CFS campaigns using endothiapepsin and the Aar2/RNaseH complex yielded hit rates of 30% and 21%, respectively, and revealed versatile binding sites. Dry presentation of the libraries allows CFS campaigns to be carried out with or without the co-solvent DMSO present. Most of the hits in our validation campaigns could be reproduced also in the absence of DMSO. Consequently, CFS can be carried out more efficiently and for a wider range of conditions and targets.</p>}},
  author       = {{Wollenhaupt, Jan and Metz, Alexander and Barthel, Tatjana and Lima, Gustavo M.A. and Heine, Andreas and Mueller, Uwe and Klebe, Gerhard and Weiss, Manfred S.}},
  issn         = {{0969-2126}},
  keywords     = {{Aar2; compound library; drug design; endothiapepsin; FBDD; fragment screening; protein-protein complex; Prp8 RNaseH; X-ray crystallography}},
  language     = {{eng}},
  pages        = {{694--706}},
  publisher    = {{Cell Press}},
  series       = {{Structure}},
  title        = {{F2X-Universal and F2X-Entry : Structurally Diverse Compound Libraries for Crystallographic Fragment Screening}},
  url          = {{http://dx.doi.org/10.1016/j.str.2020.04.019}},
  doi          = {{10.1016/j.str.2020.04.019}},
  volume       = {{28}},
  year         = {{2020}},
}