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Experimental Active-Site Mapping by Fragments - Hot Spots Remote from the Catalytic Center of Endothiapepsin

Radeva, Nedyalka; Krimmer, Stefan G; Stieler, Martin; Fu, Kan; Wang, Xiaojie; Ehrmann, Frederik R; Metz, Alexander; Huschmann, Franziska U; Weiss, Manfred S and Mueller, Uwe, et al. (2016) In Journal of Medicinal Chemistry
Abstract

Successful optimization of a given lead scaffold requires thorough binding-site mapping of the target protein particular in regions remote from the catalytic center where high conservation across protein families is given. We screened a 361-entry fragment library for binding to the aspartic protease endothiapepsin by crystallography. This enzyme is frequently used as surrogate for the design of renin and ß-secretase inhibitors. A hit rate of 20% was achieved providing 71 crystal structures. Here, we discuss 45 binding poses of fragments accommodated in pockets remote from the catalytic dyad. Three major hot-spots are discovered in remote binding areas: Asp81, Asp119, and Phe291. Compared to the dyad binders, bulkier fragments occupy... (More)

Successful optimization of a given lead scaffold requires thorough binding-site mapping of the target protein particular in regions remote from the catalytic center where high conservation across protein families is given. We screened a 361-entry fragment library for binding to the aspartic protease endothiapepsin by crystallography. This enzyme is frequently used as surrogate for the design of renin and ß-secretase inhibitors. A hit rate of 20% was achieved providing 71 crystal structures. Here, we discuss 45 binding poses of fragments accommodated in pockets remote from the catalytic dyad. Three major hot-spots are discovered in remote binding areas: Asp81, Asp119, and Phe291. Compared to the dyad binders, bulkier fragments occupy these regions. Many of the discovered fragments suggest an optimization concept on how to grow them into larger ligands occupying adjacent binding pockets that will possibly endow them with the desired selectivity for one given member of a protein family.

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publication status
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Journal of Medicinal Chemistry
publisher
The American Chemical Society
external identifiers
  • Scopus:84983628473
ISSN
1520-4804
DOI
10.1021/acs.jmedchem.6b00645
language
English
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no
id
dcd1114c-9466-485d-83e6-f9a80df18701
date added to LUP
2016-08-05 08:08:32
date last changed
2016-11-27 04:42:00
@misc{dcd1114c-9466-485d-83e6-f9a80df18701,
  abstract     = {<p>Successful optimization of a given lead scaffold requires thorough binding-site mapping of the target protein particular in regions remote from the catalytic center where high conservation across protein families is given. We screened a 361-entry fragment library for binding to the aspartic protease endothiapepsin by crystallography. This enzyme is frequently used as surrogate for the design of renin and ß-secretase inhibitors. A hit rate of 20% was achieved providing 71 crystal structures. Here, we discuss 45 binding poses of fragments accommodated in pockets remote from the catalytic dyad. Three major hot-spots are discovered in remote binding areas: Asp81, Asp119, and Phe291. Compared to the dyad binders, bulkier fragments occupy these regions. Many of the discovered fragments suggest an optimization concept on how to grow them into larger ligands occupying adjacent binding pockets that will possibly endow them with the desired selectivity for one given member of a protein family.</p>},
  author       = {Radeva, Nedyalka and Krimmer, Stefan G and Stieler, Martin and Fu, Kan and Wang, Xiaojie and Ehrmann, Frederik R and Metz, Alexander and Huschmann, Franziska U and Weiss, Manfred S and Mueller, Uwe and Schiebel, Johannes and Heine, Andreas and Klebe, Gerhard},
  issn         = {1520-4804},
  language     = {eng},
  month        = {07},
  publisher    = {ARRAY(0x8757880)},
  series       = {Journal of Medicinal Chemistry},
  title        = {Experimental Active-Site Mapping by Fragments - Hot Spots Remote from the Catalytic Center of Endothiapepsin},
  url          = {http://dx.doi.org/10.1021/acs.jmedchem.6b00645},
  year         = {2016},
}