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© Research
Publication : Proceedings of the National Academy of Sciences of the United States of America

Design of protein membrane interaction inhibitors by virtual ligand screening, proof of concept with the C2 domain of factor V

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Proceedings of the National Academy of Sciences of the United States of America - 23 Jul 2007

Segers K, Sperandio O, Sack M, Fischer R, Miteva MA, Rosing J, Nicolaes GA, Villoutreix BO

Link to Pubmed [PMID] – 17646652

Proc. Natl. Acad. Sci. U.S.A. 2007 Jul;104(31):12697-702

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.

http://www.ncbi.nlm.nih.gov/pubmed/17646652