title: Nitrogen-containing bisphosphonates as carbocation transition state analogs for isoprenoid biosynthesis.
abstract: Nitrogen-containing bisphosphonates are potent bone antiresorptive agents as well as having herbicidal and antiparasitic activity, and are thought to act by inhibiting enzymes of the mevalonate pathway. Using molecular modeling and ab initio quantum chemical calculations, we show that bisphosphonates can act as aza-isoprenoid transition state analogs, thereby inhibiting isoprenoid biosynthesis. The two phosphonate groups of the 1,1-bisphosphonates readily dock into the diphosphate-Mg(2+) binding site in farnesyl diphosphate synthase, while the charged ammonium (or pyridinium or imidazolium) groups act as carbocation transition state analogs, whose binding is stabilized by a cluster of oxygen atoms in the active site cleft, and an overall negative electrostatic potential in this region. Enhanced activity is shown to correlate with increasing van der Waals stabilization due to N-alkylation, or the presence of a charged, planar (sp(2)-hybridized) aromatic residue in the carbocation binding site. These results are of general interest since they suggest a rational approach to bisphosphonate drug design.
authors.affiliation: Departments of Chemistry and Biophysics, University of Illinois at Urbana-Champaign, 600 South Mathew's Avenue, Urbana, Illinois 61801, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Martin
authors.forename: W
authors.initials: W
authors.lastname: Arnold
authors.forename: H T
authors.initials: HT
authors.lastname: Heath
authors.forename: J A
authors.initials: JA
authors.lastname: Urbina
authors.forename: E
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000737:chemistry / Q000378:metabolism; D000478:Alkylation; D001665:Binding Sites; D001862:Bone Resorption / Q000517:prevention & control; D004164:Diphosphonates / Q000737:chemistry*; D051228:Geranyltranstransferase; D008274:Magnesium / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011106:Polyisoprenyl Phosphates / Q000096:biosynthesis* / Q000737:chemistry*; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D004164:Diphosphonates; D011106:Polyisoprenyl Phosphates; D019883:Alkyl and Aryl Transferases; D051228:Geranyltranstransferase; D008274:Magnesium