Design of protein–membrane interaction inhibitors by virtual ligand screening, proof of concept with the C2 domain of factor V
- 31 July 2007
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 104 (31), 12697-12702
- https://doi.org/10.1073/pnas.0701051104
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.Keywords
This publication has 44 references indexed in Scilit:
- Streamlining lead discovery by aligning in silico and high-throughput screeningCurrent Opinion in Chemical Biology, 2006
- FAF-Drugs: free ADME/tox filtering of compound collectionsNucleic Acids Research, 2006
- Structural Bioinformatics Prediction of Membrane-binding ProteinsJournal of Molecular Biology, 2006
- Predicting protein druggabilityDrug Discovery Today, 2005
- Virtual screening of chemical librariesNature, 2004
- Disruption of Protein-Membrane Binding and Identification of Small-Molecule Inhibitors of Coagulation Factor VIIICell Chemical Biology, 2004
- Surflex: Fully Automatic Flexible Molecular Docking Using a Molecular Similarity-Based Search EngineJournal of Medicinal Chemistry, 2003
- Virtual screening: a real screening complement to high-throughput screeningBiochemical Society Transactions, 2002
- The Protein Data BankNucleic Acids Research, 2000
- Mutations in a potential phospholipid binding loop in the C2 domain of factor V affecting the assembly of the prothrombinase complexBlood Coagulation & Fibrinolysis, 2000