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Exploiting protein fluctuations at the active-site gorge of human cholinesterases: further optimization of the design strategy to develop extremely potent inhibitors.

Journal of medicinal chemistry (2008-05-16)
Stefania Butini, Giuseppe Campiani, Marianna Borriello, Sandra Gemma, Alessandro Panico, Marco Persico, Bruno Catalanotti, Sindu Ros, Margherita Brindisi, Marianna Agnusdei, Isabella Fiorini, Vito Nacci, Ettore Novellino, Tatyana Belinskaya, Ashima Saxena, Caterina Fattorusso
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Propidium iodide solution, solution (1.0 mg/ml in water)
Sigma-Aldrich
Diisopropylfluorophosphate
Sigma-Aldrich
Propidium iodide, ≥94.0% (HPLC)
Supelco
Methamidophos solution, 100 μg/mL in acetonitrile, PESTANAL®, analytical standard
Supelco
Methamidophos, PESTANAL®, analytical standard