Structural determinants of Torpedo californica acetylcholinesterase inhibition by the novel and orally active carbamate based anti-alzheimer drug ganstigmine (CHF-2819).
Ganstigmine is an orally active, geneserine derived, carbamate-based acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The crystal structure of the ganstigmine conjugate with Torpedo californica acetylcholinesterase (TcAChE) has been determined at 2.40 A resolution, and a detailed structure-based analysis of the in vitro and ex vivo anti-AChE activity by ganstigmine and by new geneserine derivatives is presented. The carbamoyl moiety is covalently bound to the active-site serine, whereas the leaving group geneseroline is not retained in the catalytic pocket. The nitrogen atom of the carbamoyl moiety of ganstigmine is engaged in a key hydrogen-bonding interaction with the active site histidine (His440). This result offers an explanation for the inactivation of the catalytic triad and may account for the long duration of action of ganstigmine in vivo. The 3D structure also provides a structural framework for the design of compounds with improved binding affinity and pharmacological properties.
Bartolucci
Cecilia
C
Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Area della Ricerca di Roma, P O Box 10, I-00016 Monterotondo Stazione (Roma), Italy.
Siotto
Mariacristina
M
Ghidini
Eleonora
E
Amari
Gabriele
G
Bolzoni
Pier Tonino
PT
Racchi
Marco
M
Villetti
Gino
G
Delcanale
Maurizio
M
Lamba
Doriano
D
D000110:Acetylcholinesterase / Q000737:chemistry / Q000187:drug effects*; D000284:Administration, Oral; D000470:Alkaloids / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000201:enzymology; D002219:Carbamates / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D003460:Crystallization; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014101:Torpedo
D000470:Alkaloids; D002219:Carbamates; D002800:Cholinesterase Inhibitors; C060406:geneserine; D000110:Acetylcholinesterase; C447079:ganstigmine