Exploiting protein fluctuations at the active-site gorge of human cholinesterases: further optimization of the design strategy to develop extremely potent inhibitors.
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.
Butini
Stefania
S
European Research Centre for Drug Discovery and Development (NatSynDrugs), Università di Siena, Siena, Italy.
Campiani
Giuseppe
G
Borriello
Marianna
M
Gemma
Sandra
S
Panico
Alessandro
A
Persico
Marco
M
Catalanotti
Bruno
B
Ros
Sindu
S
Brindisi
Margherita
M
Agnusdei
Marianna
M
Fiorini
Isabella
I
Nacci
Vito
V
Novellino
Ettore
E
Belinskaya
Tatyana
T
Saxena
Ashima
A
Fattorusso
Caterina
C
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
D002800:Cholinesterase Inhibitors; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase