Advanced

High-Throughput Crystallography : Reliable and Efficient Identification of Fragment Hits

Schiebel, Johannes; Krimmer, Stefan G; Röwer, Karine; Knörlein, Anna; Wang, Xiaojie; Park, Ah Young; Stieler, Martin; Ehrmann, Frederik R; Fu, Kan and Radeva, Nedyalka, et al. (2016) In Structure 24(8). p.409-1398
Abstract

Today the identification of lead structures for drug development often starts from small fragment-like molecules raising the chances to find compounds that successfully pass clinical trials. At the heart of the screening for fragments binding to a specific target, crystallography delivers structural information essential for subsequent drug design. While it is common to search for bound ligands in electron densities calculated directly after an initial refinement cycle, we raise the important question whether this strategy is viable for fragments characterized by low affinities. Here, we describe and provide a collection of high-quality diffraction data obtained from 364 protein crystals treated with diverse fragments. Subsequent data... (More)

Today the identification of lead structures for drug development often starts from small fragment-like molecules raising the chances to find compounds that successfully pass clinical trials. At the heart of the screening for fragments binding to a specific target, crystallography delivers structural information essential for subsequent drug design. While it is common to search for bound ligands in electron densities calculated directly after an initial refinement cycle, we raise the important question whether this strategy is viable for fragments characterized by low affinities. Here, we describe and provide a collection of high-quality diffraction data obtained from 364 protein crystals treated with diverse fragments. Subsequent data analysis showed that ∼25% of all hits would have been missed without further refining the resulting structures. To enable fast and reliable hit identification, we have designed an automated refinement pipeline that will inspire the development of optimized tools facilitating the successful application of fragment-based methods.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Fragment screening, Synchrotron Radiation, Drug discovery
in
Structure
volume
24
issue
8
pages
12 pages
publisher
Cell Press
external identifiers
  • Scopus:84979966787
ISSN
0969-2126
DOI
10.1016/j.str.2016.06.010
language
English
LU publication?
no
id
6e0b5c32-962c-4556-aa3d-0fd03bb9cfde
date added to LUP
2016-08-05 08:14:13
date last changed
2016-11-27 04:42:01
@misc{6e0b5c32-962c-4556-aa3d-0fd03bb9cfde,
  abstract     = {<p>Today the identification of lead structures for drug development often starts from small fragment-like molecules raising the chances to find compounds that successfully pass clinical trials. At the heart of the screening for fragments binding to a specific target, crystallography delivers structural information essential for subsequent drug design. While it is common to search for bound ligands in electron densities calculated directly after an initial refinement cycle, we raise the important question whether this strategy is viable for fragments characterized by low affinities. Here, we describe and provide a collection of high-quality diffraction data obtained from 364 protein crystals treated with diverse fragments. Subsequent data analysis showed that ∼25% of all hits would have been missed without further refining the resulting structures. To enable fast and reliable hit identification, we have designed an automated refinement pipeline that will inspire the development of optimized tools facilitating the successful application of fragment-based methods.</p>},
  author       = {Schiebel, Johannes and Krimmer, Stefan G and Röwer, Karine and Knörlein, Anna and Wang, Xiaojie and Park, Ah Young and Stieler, Martin and Ehrmann, Frederik R and Fu, Kan and Radeva, Nedyalka and Krug, Michael and Huschmann, Franziska U and Glöckner, Steffen and Weiss, Manfred S and Mueller, Uwe and Klebe, Gerhard and Heine, Andreas},
  issn         = {0969-2126},
  keyword      = {Fragment screening,Synchrotron Radiation,Drug discovery},
  language     = {eng},
  month        = {08},
  number       = {8},
  pages        = {409--1398},
  publisher    = {ARRAY(0x993d360)},
  series       = {Structure},
  title        = {High-Throughput Crystallography : Reliable and Efficient Identification of Fragment Hits},
  url          = {http://dx.doi.org/10.1016/j.str.2016.06.010},
  volume       = {24},
  year         = {2016},
}