Butini Stefania, Campiani Giuseppe, Borriello Marianna, Gemma Sandra, Panico Alessandro, Persico Marco, Catalanotti Bruno, Ros Sindu, Brindisi Margherita, Agnusdei Marianna, Fiorini Isabella, Nacci Vito, Novellino Ettore, Belinskaya Tatyana, Saxena Ashima, Fattorusso Caterina
European Research Centre for Drug Discovery and Development (NatSynDrugs), Università di Siena, Siena, Italy.
J Med Chem. 2008 Jun 12;51(11):3154-70. doi: 10.1021/jm701253t. Epub 2008 May 15.
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.
蛋白质构象波动对生物学功能至关重要，尽管蛋白质运动与功能之间的关系尚未得到充分探索。通过对胆碱酯酶（ChEs）进行全面的生物信息学分析，我们确定了负责蛋白质波动和功能的特定热点，以及那些在调节关键亚结构之间的协同网络中起作用的活性位点残基。这促使我们优化设计策略，以发现能与特定蛋白质亚结构选择性相互作用的人类乙酰胆碱酯酶和丁酰胆碱酯酶（hAChE和hBuChE）的强效且可逆的抑制剂。因此，研究了由功能化连接子以不同间距隔开的两个三环部分作为分子尺度，以探测与hChE峡谷中特定热点的最精细相互作用。确定了许多构效关系趋势，并且发现多位点抑制剂3a和3d是迄今为止已知的hBuChE和hAChE的最有效抑制剂。
