Nitrogen-containing bisphosphonates as carbocation transition state analogs for isoprenoid biosynthesis

Nitrogen-containing bisphosphonates are potent bone antiresorptive agents a s well as having herbicidal and antiparasitic activity, and are thought to act by inhibiting enzymes of the mevalonate pathway. Using molecular modeli ng and ab initio quantum chemical calculations, une show that bisphosphonat es can act as aza-isoprenoid transition state analogs, thereby inhibiting i soprenoid biosynthesis, The two phosphonate groups of the 1,1-bisphosphonat es readily dock into the diphosphate-Mg2+ binding site in farnesyl diphosph ate synthase, while the charged ammonium (or pyridinium or imidazolium) gro ups act as carbocation transition state analogs, whose binding is stabilize d by a cluster of oxygen atoms in the active site cleft, and an overall neg ative 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 i n the carbocation binding site. These results are of general interest since they suggest a rational approach to bisphosphonate drug design. (C) Academ ic Press.