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Zarzycka, B.* ; Seijkens, T.* ; Nabuurs, S.B.* ; Ritschel, T.* ; Grommes, J.* ; Soehnlein, O.* ; Schrijver, R.S.* ; van Tiel, C.M.* ; Hackeng, T.M.* ; Weber, C.* ; Giehler, F. ; Kieser, A. ; Lutgens, E.* ; Vriend, G.* ; Nicolaes, G.A.F.*

Discovery of small molecule CD40-TRAF6 inhibitors.

J. Chem. Inf. Model. 55, 294-307 (2015)
Verlagsversion DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
The CD154-CD40 receptor complex plays a pivotal role in several inflammatory pathways. Attempts to inhibit the formation of this complex have resulted in systemic side effects. Downstream inhibition of the CD40 signaling pathway therefore seems a better way to ameliorate inflammatory disease. To relay a signal, the CD40 receptor recruits adapter proteins called tumor necrosis factor receptor-associated factors (TRAFs). CD40-TRAF6 interactions are known to play an essential role in several inflammatory diseases. We used in silico, in vitro, and in vivo experiments to identify and characterize compounds that block CD40-TRAF6 interactions. We present in detail our drug docking and optimization pipeline and show how we used it to find lead compounds that reduce inflammation in models of peritonitis and sepsis. These compounds appear to be good leads for drug development, given the observed absence of side effects and their demonstrated efficacy for peritonitis and sepsis in mouse models.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Protein Data-bank; Monoclonal-antibody; Drug Development; Innate Immunity; Cd40 Ligand; Surflex; Docking; Similarity; Mechanism; Obesity
Sprache englisch
Veröffentlichungsjahr 2015
HGF-Berichtsjahr 2015
ISSN (print) / ISBN 0021-9576
e-ISSN 1520-5142
Zeitschrift Journal of Chemical Information and Modeling
Quellenangaben Band: 55, Heft: 2, Seiten: 294-307 Artikelnummer: , Supplement: ,
Verlag American Chemical Society (ACS)
Verlagsort Washington
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Gene Vector (AGV)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501500-005
G-501500-001
PubMed ID 25622654
DOI 10.1021/ci500631e
WOS ID WOS:000349943100010
Scopus ID 84923377424
Erfassungsdatum 2015-02-20
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