NR AXVT
AU Salonen,E.
TI Effects and Binding of Quinacrine, Chlorpromazine, and 9-Aminoacridine on the Human Prion Protein - A Molecular Dynamics Study
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Protein Misfolding P01.31
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Prion diseases are invariably fatal with currently no practical means for diagnosis or effective treatment. Over the years a number of transmissible spongiform encephalopathy (TSE) drug candidates have been proposed, chosen mainly from a large pool of compounds whose use in the treatment of some other diseases has been established, along with a knowledge of the safe clinical doses of administration [1]. However, what is almost completely lacking at the moment is the fundamental understanding of the effects of TSE drug candidates on the different forms of prion proteins at the atomistic level. Yet, as is the case for many other diseases, it is just this information that holds the key to understanding how the pertaining drugs function and how more efficient drugs can be further designed.
We use molecular dynamics computer simulations to study, at the atomistic level, the interaction of a human prion protein (huPrPc) precursor (residues 125 - 228 at pH 7.0 [2]) with TSE drug candidates. In this initial study we have considered the interaction of huPrPc with quinacrine (QA) and chlorpromazine (CPZ), which have been used for decades to treat malaria and schizophrenia, respectively, and are known to inhibit the conversion of PrPc to the disease-related form PrPsc [3]. We identify the binding sites of these compounds on the huPrPc, along with possible changes in the structure and dynamics of the protein. The modelling is further complemented by comparing the results obtained with QA and CPZ to those obtained with 9-aminoacridine. The latter is a compound related to QA but which, on the other hand, is known not to inhibit the conversion of PrPc to PrPsc [3].
[1] C. Weissmann and A. Aguzzi, Annu. Rev. Med. 56 (2005) 321. [2] L. Calzolai and R. Zahn, J. Biol.Chem. 278 (2003) 35592; Protein Data Bank (www.rcsb.org/pdb/) entry 1HJM. [3] C. Korth, B. C. H. May, F. E. Cohen, and S. B. Prusiner, Proc. Natl. Acad. Sci. USA 98 (2001) 9836.
AD E. Salonen, Helsinki University of Technology, Laboratory of Physics, Finland
SP englisch
PO Schottland