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

• Published in: Journal of medicinal chemistry Vol. 48; no. 6; pp. 1919 - 1929
• Main Authors: Campiani, Giuseppe, Fattorusso, Caterina, Butini, Stefania, Gaeta, Alessandra, Agnusdei, Marianna, Gemma, Sandra, Persico, Marco, Catalanotti, Bruno, Savini, Luisa, Nacci, Vito, Novellino, Ettore, Holloway, Harold W, Greig, Nigel H, Belinskaya, Tatyana, Fedorko, James M, Saxena, Ashima
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.03.2005; Amer Chemical Soc
• Subjects: Acetylcholinesterase - metabolism; Acridines - chemical synthesis; Acridines - chemistry; Acridines - pharmacology; Binding Sites; Biological and medical sciences; Butyrylcholinesterase - chemistry; Butyrylcholinesterase - metabolism; Chemistry, Medicinal; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Drug Design; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Ligands; Medical sciences; Models, Molecular; Molecular Probes; Neuropharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Science & Technology; Structure-Activity Relationship; SIMULATIONS; ACETYLCHOLINESTERASE; CHOLINESTERASES; BINDING; Alzheimer disease; Nitrogen heterocycle; Acridine derivatives; Active site; Esterases; Selectivity; Modeling; Organic sulfide; Amine; Structure activity relation; Molecular model; Degenerative disease; Aromatic compound; Molecular probe; Anticholinesterase agent; Chemical synthesis; Human; Nervous system diseases; Enzyme; Enzyme inhibitor; Inhibitor enzyme complex; Antialzheimer agent; Tricyclic compound; Cholinesterase; Carboxylic ester hydrolases; Cerebral disorder; Central nervous system disease; Hydrolases; Carboxamide
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049510k

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.