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Active Site Mapping...
Active Site Mapping of an Aspartic Protease by Multiple Fragment Crystal Structures : Versatile Warheads to Address a Catalytic Dyad
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- Radeva, Nedyalka (författare)
- Philipp University of Marburg
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- Schiebel, Johannes (författare)
- Philipp University of Marburg
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- Wang, Xiaojie (författare)
- Philipp University of Marburg
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- Krimmer, Stefan G. (författare)
- Philipp University of Marburg
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- Fu, Kan (författare)
- Philipp University of Marburg
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- Stieler, Martin (författare)
- Philipp University of Marburg
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- Ehrmann, Frederik R. (författare)
- Philipp University of Marburg
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- Metz, Alexander (författare)
- Philipp University of Marburg
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- Rickmeyer, Thomas (författare)
- Philipp University of Marburg
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- Betz, Michael (författare)
- Philipp University of Marburg
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- Winquist, Johan (författare)
- Philipp University of Marburg
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- Park, Ah Young (författare)
- Philipp University of Marburg
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- Huschmann, Franziska U. (författare)
- Helmholtz Association of German Research Centers,Philipp University of Marburg
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- Weiss, Manfred S. (författare)
- Helmholtz Association of German Research Centers
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- Müller, Uwe (författare)
- Lund University,Lunds universitet,MAX IV-laboratoriet,MAX IV Laboratory,Helmholtz Association of German Research Centers
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- Heine, Andreas (författare)
- Philipp University of Marburg
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- Klebe, Gerhard (författare)
- Philipp University of Marburg
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(creator_code:org_t)
- 2016-10-28
- 2016
- Engelska 17 s.
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:21, s. 9743-9759
- Relaterad länk:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
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- art (ämneskategori)
- ref (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Radeva, Nedyalka
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Schiebel, Johann ...
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Wang, Xiaojie
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Krimmer, Stefan ...
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Fu, Kan
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Stieler, Martin
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visa fler...
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Ehrmann, Frederi ...
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Metz, Alexander
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Rickmeyer, Thoma ...
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Betz, Michael
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Winquist, Johan
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Park, Ah Young
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Huschmann, Franz ...
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Weiss, Manfred S ...
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Müller, Uwe
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Heine, Andreas
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Klebe, Gerhard
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Läkemedelskemi
- Artiklar i publikationen
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Journal of Medic ...
- Av lärosätet
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Lunds universitet