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Since reaching
a mature state 2003 Graffinity's technology has been
successfully
applied to > 85 target
proteins covering various target classes. Two representative case
studies are
described in the following publications:
Thrombin
inhibitor program
Discovery
of Thrombin Inhibitor Fragments from Chemical Microarray
Screening
Authors:
Neumann,
Thomas; Junker, Hans-Dieter; Keil, Oliver; Burkert, Klaus;
Ottleben, Holger; Gamer, Jurgen; Sekul, Renate; Deppe, Holger; Feurer,
Achim; Tomandl, Dirk; Metz, Gunther
Abstract:
Surface plasmon resonance imaging, a
low affinity screening method, allows the highly parallel detection of
small molecules binding to a target protein. The screening of a
fragment based compound library immobilized on chemical microarrays
resulted in the discovery of binding fragments for the serine protease
thrombin. Functional assays confirmed enzymatic inhibition of
microarray hits and crystallography established the binding mode of a
non-basic S1 motif providing a starting point for medicinal chemistry.
Source:
Letters
in Drug Design & Discovery,
Volume
2, Number
8, December 2005 , pp. 590-594(5)
( Paper A)
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Identification
of MMP13 Inhibitors
Improving
potency and selectivity of a new class of non-Zn-chelating MMP-13
inhibitors
I
Authors:
Heim-Riether, Alxander; Taylor, Steven J.; Liang, Shuang; Gao, Donghong
Amy; Xiong, Zhaoming; August, E. Michael;
Collins, Brandon K.; Farmer II, Bennett T.; Haverty, Kathleen;
Hill-Drzewi, Melissa; Junker, Hans-Dieter; Margarit, S. Mariana; Moss,
Neil; Neumann, Thomas; Proudfoot,John R.; Smith Keenan, Lana; Sekul,
Renate; Zhang, Qiang;
Li, Jun; Farrow, Neil A.
Abstract:
Discovery and
optimization of potency
and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of
protein co-crystal structural information is reported. This inhibitor
was observed to have a binding mode distinct from previously published
MMP-13 inhibitors. Potency and selectivity were improved by extending
the hit structure out from the active site into the S1′ pocket.
Source:
Bioorganic & Medicinal Chemistry Letters
Volume
19, Issue 18,
15 September 2009,
Pages 5321-5324
(
Paper
B)
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•
Fragment screening applied
•
Novel fragments identified
• SAR built upon fingerprinting data
• Class of highly potent, low nanomolar
inhibitors identified
• Efficacy in in vivo animal models
• patent applications filed
• Many more IP opportunities |
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