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

被引：62

作者：

Butini, Stefania ^{[1
,2
]}

Campiani, Giuseppe ^{[1
,2
]}

Borriello, Marianna ^{[1
,3
,4
]}

Gemma, Sandra ^{[1
,2
]}

Panico, Alessandro ^{[1
,2
]}

Persico, Marco ^{[1
,3
,4
]}

Catalanotti, Bruno ^{[1
,3
,4
]}

Ros, Sindu ^{[1
,2
]}

Brindisi, Margherita ^{[1
,2
]}

Agnusdei, Marianna ^{[1
,2
]}

Fiorini, Isabella ^{[1
,2
]}

Nacci, Vito ^{[1
,2
]}

Novellino, Ettore ^{[1
,3
,4
]}

Belinskaya, Tatyana ^{[5
]}

Saxena, Ashima ^{[5
]}

Fattorusso, Caterina ^{[1
,3
,4
]}

机构：

[1] Univ Siena, European Res Ctr Drug Discovery & Dev, NatSynDrugs, I-53100 Siena, Italy

[2] Univ Siena, Dipartimento Farmaco Chim Tecnol, I-53100 Siena, Italy

[3] Univ Naples Federico II, Dipartimento Chim Sostanze Nat, I-80131 Naples, Italy

[4] Univ Naples Federico II, Dipartimento Chim Farmaceut & Tossicol, I-80131 Naples, Italy

[5] Walter Reed Army Inst Res, Div Biochem, Silver Spring, MD 20910 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 11期

关键词：

D O I：

10.1021/jm701253t

中图分类号：

R914 [药物化学];

学科分类号：

100701 [药物化学];

摘要：

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.

引用

页码：3154 / 3170

页数：17

共 89 条

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