Investigating the hydrogen-bond acceptor site of the nicotinic pharmacophore model: A computational and experimental study using epibatidine-related molecular probes

Clelia Dallanoce, Giovanni Grazioso, Diego Yuri Pomè, Miriam Sciaccaluga, Carlo Matera, Cecilia Gotti, Sergio Fucile, Marco De Amici

Research output: Contribution to journalArticle


The binding mode of nicotinic agonists has been thoroughly investigated in the last decades. It is now accepted that the charged amino group is bound by a cation-π interaction to a conserved tryptophan residue, and that the aromatic moiety is projected into a hydrophobic pocket deeply located inside the binding cleft. A hydrogen bond donor/acceptor, maybe a water molecule solvating this receptor subsite, contributes to further stabilize the nicotinic ligands. The position of this water molecule has been established by several X-ray structures of the acetylcholine-binding protein. In this study, we computationally analyzed the role of this water molecule as a putative hydrogen bond donor/acceptor moiety in the agonist binding site of the three most relevant heteromeric (α4β2, α3β4) and homomeric (α7) neuronal nicotinic acetylcholine receptor (nAChR) subtypes. Our theoretical investigation made use of epibatidine 1 and deschloroepibatidine 2 as molecular probes, and was then extended to their analogues 3 and 4, which were subsequently synthesized and tested at the three target receptor subtypes. Although the pharmacological data for the new ligands 3 and 4 indicated a reduction of the affinity at the studied nAChRs with respect to reference agonists, a variation of the selectivity profile was clearly evidenced.

Original languageEnglish
Pages (from-to)975-987
Number of pages13
JournalJournal of Computer-Aided Molecular Design
Issue number11
Publication statusPublished - Nov 2013



  • Binding affinity
  • Docking
  • Epibatidine and analogues
  • Functional potency and selectivity
  • Molecular dynamics
  • Neuronal nicotinic acetylcholine receptors
  • Target-based drug design

ASJC Scopus subject areas

  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Computer Science Applications

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