2008/05/15 by Stefania Butini, Giuseppe Campiani, Marianna Borriello +13 · 1 citation
Medicine · Computer Science · #Cholinesterase and Neurodegenerative Diseases #Computational Drug Discovery Methods #Medicinal Plants and Neuroprotection
paper · doi:10.1021/jm701253t
openalex publication_date 2008/05/15 · openalex created_date 2016/06/24 · openalex updated_date 2026/07/01
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.