Development of molecular probes for the identification of extra interaction sites in the mid-gorge and peripheral sites of butyrylcholinesterase (BuChE). Rational design of novel, selective, and highly potent BuChE inhibitors.
Tacrine heterobivalent ligands were designed as novel and reversible inhibitors of cholinesterases. On the basis of the investigation of the active site gorge topology of butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) and by using flexible docking procedures, molecular modeling studies formulated the hypothesis of extra interaction sites in the active gorge of hBuChE, namely, a mid-gorge interaction site and a peripheral interaction site. The design strategy led to novel BuChE inhibitors, balancing potency and selectivity. Among the compounds identified, the heterobivalent ligand 4m, containing an amide nitrogen and a sulfur atom at the 8-membered tether level, is one of the most potent and selective BuChE inhibitors described to date. The novel inhibitors, bearing postulated key features, validated the hypothesis of the presence of extra interaction sites within the hBuChE active site gorge.
Campiani
Giuseppe
G
Dipartimento Farmaco Chimico Tecnologico, via Aldo Moro, and European Research Centre for Drug Discovery and Development (NatSynDrugs), Università di Siena, 53100 Siena, Italy. campiani@unisi.it
Fattorusso
Caterina
C
Butini
Stefania
S
Gaeta
Alessandra
A
Agnusdei
Marianna
M
Gemma
Sandra
S
Persico
Marco
M
Catalanotti
Bruno
B
Savini
Luisa
L
Nacci
Vito
V
Novellino
Ettore
E
Holloway
Harold W
HW
Greig
Nigel H
NH
Belinskaya
Tatyana
T
Fedorko
James M
JM
Saxena
Ashima
A
D000110:Acetylcholinesterase / Q000378:metabolism; D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D015335:Molecular Probes; D013329:Structure-Activity Relationship
D000166:Acridines; D002800:Cholinesterase Inhibitors; D008024:Ligands; D015335:Molecular Probes; C500068:N-(3-(1,2,3,4-tetrahydroacridin-9-ylamino)propyl)-N'-(4-(1,2,3,4-tetrahydroacridin-9-ylsulfanyl)butyl)acetamide; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase