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.

The Chemical Space Project

“…92 Starting from the fact that 322 compounds from GDB-13 also annotated as nicotinic acetylcholine receptor activity in ChEMBL were much closer to nicotine in MQN-space (CBD MQN = 22.8 ± 12.5) than average GDB-13 molecules (CBD MQN = 38.8 ± 11.1), a nearest neighbor selection was performed in the simplicity-selected GDB-13 subset (Table 1), leading to 31 504 nicotine analogs. Sixty of these were purchased from a commercial source and tested against the α7 nAChR, revealing a single agonist as the known neonicotine rac-21, and several previously unknown inhibitors such as the benzylic amine 22 and the aliphatic amidine 23, both of which are structurally quite distinct from nicotine ( Figure 5).…”

On Exploring Structure–Activity Relationships

“…While the database does not contain activity information associated with the structures, it can be used a source of structures for virtual screening purposes [50]. In this sense, it is similar in nature to databases such as ZINC [51] - the key differentiator is that the latter are all commercially available, whereas the former are in effect, completely virtual.…”

Les chimiothèques et le criblage virtuel

“…La contrepartie est la nécessité de synthétiser les molé-cules sélectionnées lors du criblage, ce qui impose bien souvent l'élimination de molécules potentiellement intéressantes, mais dont les voies d'accès synthétiques sont complexes, longues et coûteuses. Le criblage virtuel de ces chimiothèques a néanmoins conduit à des touches confirmées expérimentalement mais souvent d'affinité modeste [20]. Ce paradoxe est identique à celui rencontré lors de criblage par la méthode de design de novo [21].…”