Exploring α7-Nicotinic Receptor Ligand Diversity by Scaffold Enumeration from the Chemical Universe Database GDB.

Abstract

Virtual analogues (1167860 compounds) of the nicotinic α7-receptor (α7 nAChR) ligands PNU-282,987 and SSR180711 were generated from the chemical universe database GDB-11 by extracting all aliphatic diamine analogues of the aminoquinuclidine and 1,4-diazabicyclo[3.2.2]nonane scaffolds of these ligands and converting them to the corresponding aryl amides using five different aromatic acyl groups. The library was ranked by docking to the nicotinic binding site of the acetylcholine binding protein (AChBP, 1UW6.pdb) using Autodock and Glide. Thirty-eight ligands derived from the best docking hits were synthesized and tested for modulation of the acetylcholine signal at the human α7 nAChR receptor expressed in Xenopus oocytes, leading to competitive and noncompetitive antagonists with IC50 = 5-7 μM. These experiments demonstrate the first example of using GDB in a fragment-based approach by diversifying the scaffold of known drugs.