Three-dimensional structure of a complex of galanthamine (Nivalin (R)) with acetylcholinesterase from Torpedo californica: Implications for the design of new anti-Alzheimer drugs

The 3D structure of a complex of the anti-Alzheimer drug galanthamine with Torpedo californica acetylcholinesterase is reported. Galanthamine, a terti ary alkaloid extracted from several species of Amarylidacae, is so far the only drug that shows a dual activity, being both an acetylcholinesterase in hibitor and an allosteric potentiator of the nicotinic response induced by acetylcholine and competitive agonists, The X-ray structure, at 2.5 Angstro m resolution, shows an unexpected orientation of the ligand within the acti ve site, as well as unusual protein-ligand interactions. The inhibitor bind s at the base of the active site gorge, interacting with both the acyl-bind ing pocket and the principal quaternary ammonium-binding site. However, the tertiary amine group of galanthamine does not directly interact with Trp84 , A docking study using the program AUTODOCK correctly predicts the orienta tion of galanthamine in the active site. The docked lowest-energy structure has a root mean square deviation of 0.5 Angstrom with respect to the corre sponding crystal structure of the complex, The observed binding mode explai ns the affinities of a series of structural analogs of galanthamine and pro vides a rational basis for structure-based drug design of synthetic derivat ives with improved pharmacological properties. Proteins 2001;42:182-191. (C ) 2000 Wiley-Liss, Inc.