Docking studies of benzylidene anabaseine interactions with α7 nicotinic acetylcholine receptor (nAChR) and acetylcholine binding proteins (AChBPs): Application to the design of related α7 selective ligands

Abstract

AChBPs isolated from Lymnaea stagnalis (Ls), Aplysia californica (Ac) and Bulinus truncatus (Bt) have been extensively used as structural prototypes to understand the molecular mechanisms that underlie ligand-interactions with nAChRs [1]. Here, we describe docking studies on interactions of benzylidene anabaseine analogs with AChBPs and α7 nAChR. Results reveal that docking of these compounds using Glide software accurately reproduces experimentally-observed binding modes of DMXBA and of its active metabolite, in the binding pocket of Ac. In addition to the well-known nicotinic pharmacophore (positive charge, hydrogen-bond acceptor, and hydrophobic aromatic groups), a hydrogen-bond donor feature contributes to binding of these compounds to Ac, Bt, and the α7 nAChR. This is consistent with benzylidene anabaseine analogs with OH and NH2 functional groups showing the highest binding affinity of these congeners, and the position of the ligand shown in previous X-ray crystallographic studies of ligand-Ac complexes. In the predicted ligand-Ls complex, by contrast, the ligand OH group acts as hydrogen-bond acceptor. We have applied our structural findings to optimizing the design of novel spirodiazepine and spiroimidazoline quinuclidine series. Binding and functional studies revealed that these hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the α7 nAChR subtype and demonstrate partial agonism. The gain in affinity is also due to conformational restriction, tighter hydrophobic enclosures, and stronger cation-π interactions. The use of AChBPs structure as a surrogate to predict binding affinity to α7 nAChR has also been investigated. On the whole, we found that molecular docking into Ls binding site generally scores better than when a α7 homology model, Bt or Ac crystal structure is used.

Molecular Dynamics Simulations Study on the Resistant Mechanism of Insects to Imidacloprid due to Y151‐S and R81T Mutations in nAChRs

“…The Ls‐AChBP structure was successfully used as a template for homology models of LBD regions of nAChRs, and these models were further developed to study receptor‐ligand interactions and to design new small molecules for nAChRs . In addition, Ls‐AChBP also acts as a substitute for nAChR to study the interaction with small molecules . So, it is reasonable to use Ls‐AChBP to simulate the LBD of nAChR.…”

Physical and virtual screening methods for marine toxins and drug discovery targeting nicotinic acetylcholine receptors

“…Ligand-based and receptor-based pharmacophoric models were described, and in conjunction with docking calculations allowed the design of novel a7 selective spirodiazepine and spiroimidazoline quinuclidines [128,129], a7 selective arylideneanabaseine derivatives [130], Aconitum and Delpinium diterpenoid alkaloids [131] and a4b2 selective methyllycaconitine-derived negative allosteric modulators [132,133].…”

Discovery of (2S,3R)-N-[2-(Pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]benzo[b]furan-2-carboxamide (TC-5619), a Selective α7 Nicotinic Acetylcholine Receptor Agonist, for the Treatment of Cognitive Disorders

“…Docking was carried out as previously described. 52 In a nutshell, using the protein preparation wizard module, hydrogen-bonding assignment was optimized and protein−ligand complex was energy-minimized to a root-mean-square deviation (rmsd) of 0.30 Å. Standard protonation state at physiological pH was used for all ligands, i.e., the quinuclidine nitrogen was treated as protonated.…”