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.

Design of novel α7-subtype-preferring nicotinic acetylcholine receptor agonists: application of docking and MM-PBSA computational approaches, synthetic and pharmacological studies / G. Grazioso, D.Y. Pomè, C. Matera, F. Frigerio, L. Pucci, C. Gotti, C. Dallanoce, M. De Amici. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 19:22(2009), pp. 6353-6357.

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

G. Grazioso
;
C. Matera;F. Frigerio;L. Pucci;C. Dallanoce
Penultimo
;
M. De Amici
Ultimo
2009

Abstract

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.
MM-PBSA; Neuronal nicotinic acetylcholine receptors; alpha 7 Selective nicotinic agonists; Binding affinity
Settore CHIM/08 - Chimica Farmaceutica
Nuovi ligandi selettivi dei recettori nicotinici neuronali omomerici ed eteromerici: progettazione, sintesi, indagine bio-farmacologica e relazioni struttura/attività.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/69687
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