Assessing the chemical and biological diversity of an ion channels knowledge database.

The aim of the present work is to assess the chemical and biological diversity of ligands reported in scientific articles or patents to be active against ion channels targets. A specific query of the AurSCOPE Ion Channel knowledge database was constructed to retrieve a set of the most active non-peptide ligands tested in binding or electrophysiology experiments against all ion channel families. A biological activity threshold cutoff expressed by K(i), IC(50), or EC(50) was set to 300 nM. This activity cutoff was selected such that we would retrieve a set of compounds, which contain the most active ligands for all target families, but is a reasonable number to analyze. To encode the chemical space for the entire active dataset (9897 molecules), ChemAxon's chemical fingerprints were computed and optimized and then employed to cluster the dataset at a variety of different similarity thresholds. Concurrently, the exploration of the biological space was performed by associating with each chemical cluster the corresponding target or target family. Tri-dimensional visualization of different voltage- and ligand-gated ion channel families projected into the active chemical space was obtained after a principal components analysis performed using selected molecular descriptors. The findings presented herein give a global picture of the realm of ion channels active ligands and link the knowledge on chemical structures with their respective biological activities.