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Title: Design of protein-membrane interaction inhibitors by virtual ligand screening, proof of concept with the C2 domain of factor V
Authors: Segers, Kenneth ×
Sperandio, Olivier
Sack, Markus
Fischer, Rainer
Miteva, Maria A
Rosing, Jan
Nicolaes, Gerry A. F
Villoutreix, Bruno O #
Issue Date: Jul-2007
Publisher: Natl acad sciences
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:104 issue:31 pages:12697-12702
Abstract: Most orally bioavailable drugs on the market are competitive inhibitors of catalytic sites, but a significant number of targets remain undrugged, because their molecular functions are believed to be inaccessible to drug-like molecules. This observation specifically applies to the development of small-molecule inhibitors of macromolecular interactions such as protein-membrane interactions that have been essentially neglected thus far. Nonetheless, many proteins containing a membrane-targeting domain play a crucial role in health and disease, and the inhibition of such interactions therefore represents a very promising therapeutic strategy. In this study, we demonstrate the use of combined in silico structure-based virtual ligand screening and surface plasmon resonance experiments to identify compounds that specifically disrupt protein-membrane interactions. Computational analysis of several membrane-binding domains revealed they all contain a druggable pocket within their membrane-binding region. We applied our screening protocol to the second discoidin domain of coagulation factor V and screened > 300,000 drug-like compounds in silico against two known crystal structure forms. For each C2 domain structure, the top 500 molecules predicted as likely factor V-membrane inhibitors were evaluated in vitro. Seven drug-like hits were identified, indicating that therapeutic targets that bind transiently to the membrane surface can be investigated cost-effectively, and that inhibitors of protein-membrane interactions can be designed.
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Molecular Bacteriology (Rega Institute)
Laboratory for the Research of Neurodegenerative Diseases
× corresponding author
# (joint) last author

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