Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs. (Articolo in rivista)

Type

• Prodotto della ricerca (Classe)
• Articolo in rivista (Classe)

Label

• Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs. (Articolo in rivista) (literal)

Anno

• 2001-01-01T00:00:00+01:00 (literal)

Alternative label

• Bartolucci C. 1, Perola E. 2, Pilger C. 3, Fels G. 4, Lamba D. 1 (2001)
  Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs.
  in Proteins (Print)
  (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori

• Bartolucci C. 1, Perola E. 2, Pilger C. 3, Fels G. 4, Lamba D. 1 (literal)

Pagina inizio

• 182 (literal)

Pagina fine

• 191 (literal)

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• 42 (literal)

Rivista

• Proteins (Rivista)

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• 10 (literal)

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• Alzheimer’s disease (AD) is a neurodegenerative disorder of the central nervous system characterized by memory impairment, emotional disturbance and personality changes. It has been found that AD is associated with reduced levels of choline acetylcholinesterase (AChE) and nicotinic acetylcholine receptors, resulting in a dramatic dysfunction of the central cholinergic system. Aim of the drug therapeutic approach to AD is the elevation of the transient levels of acetylcholine (ACh) in the brain or direct enhancement of nicotinic receptor activation by use of cholinesterase inhibitors or nicotinic agonists. Galanthamine is a centrally acting, selective, competitive and reversible cholinesterase inhibitor that produces significant improvement in AD patients. It is one of very few drugs exhibiting dual activity, acting as an AChE inhibitor as well as an allosteric potentiator of nicotinic response induced by ACh and competitive agonists. (literal)

Note

• ISI Web of Science (WOS) (literal)

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• 1 IC-CNR, 2 Vertex Pharmaceuticals, 3 Uni Wien, 4 Uni Paderborn (literal)

Titolo

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

Abstract

• 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. (literal)

Prodotto di

• Studi strutturali e funzionali di proteine di interesse biomedico e biotecnologico (PM.P01.023.001) (Modulo)
• Institute of Crystallography (IC) (Istituto)

Autore CNR

• DORIANO LAMBA (Unità di personale interno)
• CECILIA BARTOLUCCI (Unità di personale interno)

Insieme di parole chiave

• Parole chiave di "Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs." (Insieme di parole chiave)

Incoming links:

Prodotto

• Institute of Crystallography (IC) (Istituto)
• Studi strutturali e funzionali di proteine di interesse biomedico e biotecnologico (PM.P01.023.001) (Modulo)

Autore CNR di

• DORIANO LAMBA (Unità di personale interno)
• CECILIA BARTOLUCCI (Unità di personale interno)

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• Proteins (Rivista)

Insieme di parole chiave di

• Parole chiave di "Three-dimensional structure of a complex of galanthamine (Nivalin) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs." (Insieme di parole chiave)