Binding of 13-amidohuprines to acetylcholinesterase: exploring the ligand-induced conformational change of the gly117-gly118 peptide bond in the oxyanion hole.
The acetylcholinesterase (AChE) inhibitory activity of a series of 13-amido derivatives of huprine Y, designed to enlarge the occupancy of the catalytic binding site by mimicking the piridone moiety present in (-)-huperzine A, has been assessed. Although both 13-formamido and 13-methanesulfonamido derivatives are more potent human AChE inhibitors than tacrine and (-)-huperzine A, none of them equals the potency of huprine Y. Molecular modeling studies show that the two derivatives effectively trigger the Gly117-Gly118 conformational flip induced upon binding of (-)-huperzine A, leading to a similar pattern of interactions as that formed by the pyridone amido group of (-)-huperzine A. The detrimental effect on the binding affinity relative to the 13-unsubstituted huprine could be ascribed to a sizable deformation cost associated with the ligand-induced peptide flip. This finding can be interpreted as a mechanism selected by evolution to ensure the preorganization of the functionally relevant oxyanion hole in the binding site of AChE, where residues Gly117 and Gly118 play a relevant role in mediating substrate recognition.
Camps
Pelayo
P
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal 643, E-08028, Barcelona, Spain.
Gómez
Elena
E
Muñoz-Torrero
Diego
D
Badia
Albert
A
Clos
Maria Victòria
MV
Curutchet
Carles
C
Muñoz-Muriedas
Jordi
J
Luque
Francisco Javier
FJ
D000110:Acetylcholinesterase / Q000737:chemistry*; D000470:Alkaloids; D000634:Aminoquinolines / Q000737:chemistry*; D000818:Animals; D000838:Anions; D020134:Catalytic Domain; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000737:chemistry*; D004912:Erythrocytes / Q000201:enzymology; D005559:Formamides / Q000737:chemistry; D005998:Glycine / Q000737:chemistry*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D012717:Sesquiterpenes / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D013619:Tacrine / Q000737:chemistry
D000470:Alkaloids; D000634:Aminoquinolines; D000838:Anions; D002800:Cholinesterase Inhibitors; D005559:Formamides; D006576:Heterocyclic Compounds, 4 or More Rings; D008024:Ligands; D012717:Sesquiterpenes; D013449:Sulfonamides; C404518:huprine X; C404519:huprine Y; C050426:huperzine A; D013619:Tacrine; D000110:Acetylcholinesterase; D005998:Glycine