POSTER NO: 405

The Possible Mechanism Of Action For Quinacrine Interacting with The Scrapie Protein In Prion Disease

Raymond M.W. Chau, Donald M.L. Tse
Dept of Anatomy, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong

In the computational docking of quinacrine with the scrapie protein [1B10, a Recombinant Syrian Hamster Prion Protein], we found that in the ten docking results of the lowest energies, and thus most stable, quinacrine all appear to dock at the same site, at slightly different orientations.

In all of the ten docking results the triple rings of the quinacrine molecule dock at the ring side chain of His140, the two ring structures running parallel to each other. In five of the results (R-L1,2,5,9,10) the histidine ring lies opposite the middle of the three rings of quinacrine. In the other five results the histidine ring tends to lie opposite the methoxylated ring or in between that and the middle ring. There is a possibility of hydrogen bonding between the NH group in the histidine ring and the methoxy oxygen in some cases, whereas hydrogen bonding with the N in the ring also appears possible in others.

This docking result is unusual in that the ten most stable positions of quinacrine binding to this prion all lie at the same site although at slightly different orientations. This has not been previously observed with other docking experiments, even in similar docking experiments involving a small molecule and a protein, which eliminates the doubt that the result may come from an error of the gramm program. The consistent docking of quinacrine to His140 suggests that His140 should be the site of action of quinacrine on 1B10, and thus the role of His140 in prion disease pathogenesis should be investigated in more detail.

Proposed action of Quinacrine:

As seen from the results of our docking experiments, quinacrine shows a high affinity for the residue 140, a histidine on the hairpin loop structure between the first b-strand and helix A. Since this site is not physically close to the disulphide bond or to the helices B and C, it is not immediately clear how quinacrine plays a role in the inhibition of conversion from PrPC to PrPSc. There is almost no mention of the relevance of histidine-140 in the structure of normal prion or scrapie in previous literature. What is known about histidine 140 is that it is part of a hair-pin loop structure just before the helix of residues 144-151, and that this histidine remains part of the infective PrPSc molecule. The hair-pin loop structure is suggested to be more flexible than other parts of the scrapie structure.

In order to inhibit PrPSc formation, quinacrine could either inhibit the conversion from PrPC to PrPSc, or inhibit the aggregation of PrPSc into amyloid plaques. Both of these mechanisms would inhibit the eventual pathogenesis of prion disease. Since it has been shown experimentally that the triple ring structure alone is not enough for inhibition of PrPSc formation, the side chain of quinacrine, which points outwards in the most popular docking orientation, must play a role in quinacrine activity. The role of the outward-pointing side chain is likely to be interaction with another PrPC or PrPSc molecule. As the quinacrine molecule binds to PrPC or PrPSc, histidine-140 and its surrounding amino acid residues are blocked from any potential interaction with other PrPC or PrPSc molecules. Such interaction could be in the form of a heterodimer model of conversion, or in a head-to-tail mechanism of polymerization. Since histidine-140 is also in the more planar structure of PrPSc and PrP27-30, binding of a quinacrine molecule pyramidal in shape could disrupt the attractive forces between the b-strands in adjacent planar scrapie molecules. The inability of the planar molecules to stack up would prevent polymerization from taking place.