title: 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.
authors.affiliation: Department de Química, Institut Universitari d'Investigació en Ciències de la Salut (IUNICS), Universitat de les Illes Balears, 07122, Palma de Mallorca, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Fernández
authors.forename: Joaquin
authors.initials: J
authors.lastname: Ortega-Castro
authors.forename: Laura
authors.initials: L
authors.lastname: Mariño
authors.forename: Joan
authors.initials: J
authors.lastname: Perelló
authors.forename: Juan
authors.initials: J
authors.lastname: Frau
mesh_terms: D020134:Catalytic Domain; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011522:Protons; D000068296:Risedronic Acid / Q000737:chemistry; D055672:Static Electricity; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011522:Protons; D000077211:Zoledronic Acid; D051228:Geranyltranstransferase; D000068296:Risedronic Acid