期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 130, 期 4, 页码 1264-1273出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja0759949
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资金
- NIGMS NIH HHS [GM65307] Funding Source: Medline
We report the results of an investigation of the binding of a series of bisphosphonate drugs to human bone using H-2, C-13, N-15, and P-31 nuclear magnetic resonance spectroscopy. The P-31 NMR results show that the bisphosphonate groups bind irrotationally to bone, displacing orthophosphate from the bone mineral matrix. Binding of pamidronate is well described by a Langmuir-like isotherm, from which we deduce an similar to 30-38 angstrom(2) surface area per pamidronate molecule and a Delta G = -4.3 kcal mol(-1). TEDOR of [C-13(3), N-15] pamidronate on bone shows that the bisphosphonate binds in a gauche [N-C(1)] conformation. The results of P-31 as well as N-15 shift and cross-polarization measurements indicate that risedronate binds weakly, since it has a primarily neutral pyridine side chain, whereas zoledronate (with an imidazole ring) binds more strongly, since the ring is partially protonated. The results of H-2 NMR measurements of side-chain 2 H-labeled pamidronate, alendronate, zoledronate, and risedronate on bone show that all side chains undergo fast but restricted motions. In pamidronate, the motion is well simulated by a gauche(+)/gauche(-) hopping motion of the terminal -CH2-NH3+ group, due to jumps from one anionic surface group to another. The results of double-cross polarization experiments indicate that the NH3+-terminus of pamidronate is close to the bone mineral surface, and a detailed model is proposed in which the gauche side-chain hops between two bone PO43- sites.
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