Design of novel α7-subtype-preferring nicotinic acetylcholine receptor agonists: Application of docking and MM-PBSA computational approaches, synthetic and pharmacological studies

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• 作者：Giovanni Grazioso ; Diego Yuri Pomè ; Carlo Matera ; Fabio Frigerio ; Luca Pucci ; Cecilia Gotti ; Clelia Dallanoce ; Marco De Amici
• 关键词：MM-PBSA ; Neuronal nicotinic acetylcholine receptors ; α ; 7 Selective nicotinic agonists ; Binding affinity
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2009
• 出版时间：15 November 2009
• 年：2009
• 卷：19
• 期：22
• 页码：6353-6357
• 全文大小：316 K

文摘

In the search for nicotinic acetylcholine receptor (nAChRs) agonists with a selective affinity for the homomeric α7 channels, we carried out the virtual screening of a test set of potential nicotinic ligands, and adopted a simplified MM-PBSA approach to estimate their relative binding free energy values. By means of this procedure, previously validated by a training set of compounds, we reached a realistic compromise between computational accuracy and calculation rate, and singled out a small group of novel structurally related derivatives characterized by a promising theoretical affinity for the α7 subtype. Among them, five new compounds were synthesized and assayed in binding experiments at neuronal α7 as well as α4β2 nAChRs.