POSTER NO: 456

Interaction Between Normal Prion Protein And the Drug Quinacrine

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

The computational docking of Quinacrine with the bovine prion protein fragment 1DWY using the GRAMM program shows four regions of preferential binding:

1. The outer surface of helix A which is made up of residues 144-151, where three variations of docking are shown as of low energy. The main residues involved in the docking are Arg148, Tyr149, Glu152 and Asn153. In the first position (R-L1) the triple ring of quinacrine lies on the side chains of Arg148, Tyr149, Glu152 and Asn153, while the phenol group of Tyr145 approaches the side of the methoxylated ring of quinacrine. The side chain of quinacrine points outwards. In the second position (R-L3), the two phenol groups of Tyr145 and Tyr149 surrounds the side chain of quinacrine, while the residual carbonyl of Asn153 is directly above the N within the triple ring of quinacrine. The side chain of Arg156 runs along the two rings of quinacrine from the N to the chloride group, while the carboxyl group of Glu152 points at the methoxy group of quinacrine. In the third position (R-L8), the two phenol groups of Tyr145 and Tyr149 face the ring obliquely, while the residual groups of Asn153 and Arg156 point at the triple ring from the side and the chloride group of quinacrine respectively.

2. Five of the docking results show that quinacrine binds in the space between the end of the last helix (residues 218-226) and the coil connecting the second b-strand and the second helix (residues 165-172). Again there are three positions and the main residues participating with docking are Tyr218, Glu221, Tyr225 and Tyr226. In the first position (R-L2), the phenol group of Tyr226 lies parallel to the methoxylated ring with the OH group close to the N in the ring, while the phenol ring of Tyr225 liesover the methoxy oxygen perpendicular to the triple ring. The OH group of Tyr218 points at the side chain of quinacrine. In the second position (R-L 9&10) the phenol ring of Tyr225 lies parallel over the chlorinated ring while the ring of Tyr226 approaches the methoxy oxygen from the side. In the third position (R-L 5&6), the phenol ring of Tyr225 lies parallel over the chlorinated and middle rings of quinacrine, with the oxygen directly over the center of the triple rings.

3. One docking result (R-L4) shows quinacrine docking at the region between the second helix and the coil connecting the first helix and the second b-strand. The side chains of Pro158, Asn159 and Glu160 surround the methoxylated ring in a clamp-like manner, while the side chains of His187 and Thr190 point perpendicularly at the triple rings of the quinacrine molecule.

4. One docking result (R-L7) shows the quinacrine molecule docking in a pocket formed by residues 140-144, which makes up a hair-pin loop in the prion structure. The triple rings of quinacrine fit into the groove formed by the backbone of these residues, while the outward projecting side chains of His140 and Asp144 are positioned on either side of the middle ring. The carboxylic group of Asp144 points at the N in the ring, while the NH group of the histidine ring points at the N just outside the triple ring structure.

All four regions show the potential influence of quinacrine on normal prion protein in preventing prion disease from happening. It can possibly act by obstructing the unfolding process of the normal PrPc conformer in its transformation to the disease PrPsc conformer, or by providing an anchor for two structures to bind to, such as a helix and a coil, thus stabilizing the 3D structure preventing unfolding from taking place.