Discovery of α7-Nicotinic Receptor Ligands by Virtual Screening of the Chemical Universe Database GDB-13

Abstract

The chemical universe database GDB-13 enumerates 977 million organic molecules up to 13 atoms of C, N, O, Cl, and S that are virtually possible following simple rules for chemical stability and synthetic feasibility. Analogs of nicotine were identified in GDB-13 using the city-block distance in MQN-space (CBD(MQN)) as a similarity measure, combined with a restriction eliminating problematic structural elements. The search was carried out with a Web browser available at www.gdb.unibe.ch . This virtual screening procedure selected 31 504 analogs of nicotine from GDB-13, from which 48 were known nicotinic ligands reported in Chembl. An additional 60 virtual screening hits were purchased and tested for modulation of the acetylcholine signal at the human α7 nAChR expressed in Xenopus oocytes, which led to the identification of three previously unknown inhibitors. These experiments demonstrate for the first time the use of GDB-13 for ligand discovery.

DOI: 10.1021/ci200410u

Extracted Key Phrases

9 Figures and Tables

Cite this paper

@article{Blum2011DiscoveryO, title={Discovery of α7-Nicotinic Receptor Ligands by Virtual Screening of the Chemical Universe Database GDB-13}, author={Lorenz C. Blum and Ruud van Deursen and Sonia Bertrand and Milena Mayer and Justus J. B{\"{u}rgi and Daniel Bertrand and Jean-Louis Reymond}, journal={Journal of chemical information and modeling}, year={2011}, volume={51 12}, pages={3105-12} }