Mechanistic insights into protonation state as a critical factor in hFPPS enzyme inhibition

Abstract

Zoledronate and risedronate are the most powerful available nitrogen-containing bisphosphonates used in the treatment of bone-resorption disorders. Knowledge about inhibition mechanisms of these molecules is based on available crystallographic structures of human farnesyl pyrophosphate synthase (hFPPS). However, there is a lack of information explaining the inhibition potency of these two molecules compared to the natural substrate, dimethylallyl pyrophosphate. We carried out a molecular dynamics study that shown: (1) that NBPs potency is related to higher electrostatic interactions with the metallic cluster of the active site than to the natural substrate, and (2) the protonation of the R2 side chain is a critical factor to stabilize the NBPs into a closely irreversible ternary complex with the hFPPS.

Theoretical study of the deposition and adsorption of bisphosphonates on the 001 hydroxyapatite surface: Implications in the pathological crystallization inhibition and the bone antiresorptive action

“…What is more, the presence of the positive charge on the R 2 group has been shown to be necessary to keep the hFPPS enzyme in its inhibited conformation [95].…”