Methods for computer-aided chemical biology. Part 4: selectivity searching for ion channel ligands and mapping of molecular fragments as selectivity markers.

For the computational exploration of structure-selectivity relationships, a compound selectivity system consisting of 243 antagonists of ionotropic glutamate ligand-gated ion channels was designed. Selected antagonists were organized in nine different selectivity sets. In systematic selectivity search calculations utilizing these data sets, structural fingerprints produced a significant enrichment of selective compounds over non-selective molecules and database decoys. The molecular basis of these findings was explored in detail. Fingerprint bit settings characteristic of antagonists with different selectivity profiles were identified and the corresponding structural features were correlated with sets of molecular fragments derived from selective and non-selective antagonists following a hierarchical fragmentation strategy separating aromatic and aliphatic core structure elements and substituents. This analysis rationalized the selectivity search performance of structural fingerprints and revealed structural motifs that are selectivity markers for different types of ion channel antagonists.