When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?

Traditional hit-to-lead optimization
assumes that upon elaboration of chemical structure, the ligand retains
its binding mode relative to the receptor. Here, we build a large-scale
collection of related ligand pairs solved in complex with the same
protein partner: we find that for 41 of 297 pairs (14%), the binding
mode changes upon elaboration of the smaller ligand. While certain
ligand physiochemical properties predispose changes in binding mode,
particularly those properties that define fragments, simple structure-based
modeling proves far more effective for identifying substitutions that
alter the binding mode. Some ligand pairs change binding mode because
the added substituent would irreconcilably conflict with the receptor
in the original pose, whereas others change because the added substituent
enables new, stronger interactions that are available only in a different
pose. Scaffolds that can engage their target using alternate poses
may enable productive structure-based optimization along multiple
divergent pathways.