title: Exploiting protein fluctuations at the active-site gorge of human cholinesterases: further optimization of the design strategy to develop extremely potent inhibitors.
abstract: Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase (hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), Università di Siena, Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Marianna
authors.initials: M
authors.lastname: Borriello
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
authors.forename: Alessandro
authors.initials: A
authors.lastname: Panico
authors.forename: Marco
authors.initials: M
authors.lastname: Persico
authors.forename: Bruno
authors.initials: B
authors.lastname: Catalanotti
authors.forename: Sindu
authors.initials: S
authors.lastname: Ros
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.forename: Marianna
authors.initials: M
authors.lastname: Agnusdei
authors.forename: Isabella
authors.initials: I
authors.lastname: Fiorini
authors.forename: Vito
authors.initials: V
authors.lastname: Nacci
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Tatyana
authors.initials: T
authors.lastname: Belinskaya
authors.forename: Ashima
authors.initials: A
authors.lastname: Saxena
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000737:chemistry*; D019295:Computational Biology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D002800:Cholinesterase Inhibitors; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase