title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gaeta
authors.forename: Marianna
authors.initials: M
authors.lastname: Agnusdei
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Marco
authors.initials: M
authors.lastname: Persico
authors.forename: Bruno
authors.initials: B
authors.lastname: Catalanotti
authors.forename: Luisa
authors.initials: L
authors.lastname: Savini
authors.forename: Vito
authors.initials: V
authors.lastname: Nacci
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Harold W
authors.initials: HW
authors.lastname: Holloway
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Tatyana
authors.initials: T
authors.lastname: Belinskaya
authors.forename: James M
authors.initials: JM
authors.lastname: Fedorko
authors.forename: Ashima
authors.initials: A
authors.lastname: Saxena
mesh_terms: 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
chemical_list: 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