Chirality-Driven Mode of Binding of α‑Aminophosphonic Acid-Based Allosteric Inhibitors of the Human Farnesyl Pyrophosphate Synthase (hFPPS)

Thienopyrimidine-based allosteric
inhibitors of the human farnesyl pyrophosphate synthase (hFPPS), characterized
by a chiral α-aminophosphonic acid moiety, were synthesized
as enantiomerically enriched pairs, and their binding mode was investigated
by X-ray crystallography. A general consensus in the binding orientation
of all (R)- and (S)-enantiomers
was revealed. This finding is a prerequisite for establishing a reliable
structure–activity relationship (SAR) model.