Fig. 1: Overview: target modification to explore functionally privileged chemical space.
From: C5 methylation confers accessibility, stability and selectivity to picrotoxinin
a Chemical space plot of parallel series to explore the effects of a scaffold uniquely accessible through total synthesis; (b) C5 methylation increases stability to base and acid, increases yield, decreases required steps and increases receptor selectivity; (c) Assay against GABAA and RDL receptors, representative of vertebrate (e.g. human) and invertebrate (e.g. insect) ligand-gated ion channels (LGICs), respectively. Left: rat GABAA homology model from PDB 6×40 template with sequence from R. norvegicus, gold. Right: fly RDL homology model from PDB 6×40 template with sequence from D. melanogaster, blue. d Computational analyses provide models for increased stability and selectivity of the 5MePXN series. PXN picrotoxinin, 5MePXN 5-methylpicrotoxinin.
