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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Authors: | Giovanni Grazioso Diego Yuri Pom Carlo Matera Fabio Frigerio Luca Pucci Cecilia Gotti Clelia Dallanoce Marco De Amici |
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Institution: | aDipartimento di Scienze Farmaceutiche ‘Pietro Pratesi’, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy;bCNR, Istituto di Neuroscienze, Farmacologia Cellulare e Molecolare e Dipartimento di Farmacologia, Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milano, Italy |
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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. |
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Keywords: | MM-PBSA Neuronal nicotinic acetylcholine receptors α 7 Selective nicotinic agonists Binding affinity |
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