Three-dimensional structure of a complex of galanthamine (Nivalin) 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 tertiary alkaloid extracted from several species of Amarylidacae, is so far the only drug that shows a dual activity, being both an acetylcholinesterase inhibitor and an allosteric potentiator of the nicotinic response induced by acetylcholine and competitive agonists. The X-ray structure, at 2.5A resolution, shows an unexpected orientation of the ligand within the active site, as well as unusual protein-ligand interactions. The inhibitor binds at the base of the active site gorge, interacting with both the acyl-binding 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 orientation of galanthamine in the active site. The docked lowest-energy structure has a root mean square deviation of 0.5A with respect to the corresponding crystal structure of the complex. The observed binding mode explains the affinities of a series of structural analogs of galanthamine and provides a rational basis for structure-based drug design of synthetic derivatives with improved pharmacological properties. Proteins 2001;42:182-191.
Bartolucci
C
C
Istituto di Strutturistica Chimica G. Giacomello, Monterotondo Stazione, Roma, Italy.
Perola
E
E
Pilger
C
C
Fels
G
G
Lamba
D
D
D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001665:Binding Sites; D002800:Cholinesterase Inhibitors / Q000737:chemistry; D003460:Crystallization; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000737:chemistry; D053138:Cyclohexenes; D015195:Drug Design; D005702:Galantamine / Q000737:chemistry* / Q000627:therapeutic use; D008958:Models, Molecular; D018697:Nootropic Agents / Q000737:chemistry / Q000627:therapeutic use; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014101:Torpedo / Q000378:metabolism*
D002800:Cholinesterase Inhibitors; D003510:Cyclohexanes; D053138:Cyclohexenes; D018697:Nootropic Agents; D005702:Galantamine; C052568:cyclohexene; D000110:Acetylcholinesterase