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Nitrogen-containing bisphosphonates as carbocation transition state analogs for isoprenoid biosynthesis
M B Martin1, W Arnold, H T Heath
1Departments of Chemistry and Biophysics, University of Illinois at Urbana-Champaign, 600 South Mathew's Avenue, Urbana, Illinois 61801, USA.
Biochemical and Biophysical Research Communications
|October 8, 1999
Summary
Nitrogen-containing bisphosphonates inhibit isoprenoid biosynthesis by acting as aza-isoprenoid transition state analogs. This mechanism, revealed through molecular modeling, guides rational drug design for bisphosphonate therapies.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Computational Chemistry
Background:
- Nitrogen-containing bisphosphonates are effective bone antiresorptive agents.
- They also exhibit herbicidal and antiparasitic activities.
- Their mechanism of action is believed to involve inhibition of the mevalonate pathway.
Purpose of the Study:
- To elucidate the molecular mechanism by which bisphosphonates inhibit isoprenoid biosynthesis.
- To investigate bisphosphonates as aza-isoprenoid transition state analogs.
- To provide insights for rational bisphosphonate drug design.
Main Methods:
- Molecular modeling techniques were employed.
- Ab initio quantum chemical calculations were performed.
- Binding interactions within the farnesyl diphosphate synthase active site were analyzed.
Main Results:
- Bisphosphonates function as aza-isoprenoid transition state analogs, inhibiting isoprenoid biosynthesis.
- The phosphonate groups bind to the diphosphate-Mg(2+) site of farnesyl diphosphate synthase.
- Charged nitrogen groups act as carbocation transition state analogs, stabilized by active site features.
Conclusions:
- Bisphosphonates inhibit isoprenoid biosynthesis by mimicking transition states.
- Drug design can be optimized by considering van der Waals stabilization and charged aromatic residues.
- These findings offer a rational approach for developing novel bisphosphonate drugs.