Structural features underlying raloxifene's biophysical interaction with bone matrix

Nicoletta Bivi, Haitao Hu, Balagopalakrishna Chavali, Michael J. Chalmers, Christopher T. Reutter, Gregory L. Durst, Anna Riley, Masahiko Sato, Matthew Allen, David Burr, Jeffrey A. Dodge

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Raloxifene, a selective estrogen receptor modulator (SERM), reduces fracture risk at least in part by improving the mechanical properties of bone in a cell- and estrogen receptor-independent manner. In this study, we determined that raloxifene directly interacts with the bone tissue. Through the use of multiple and complementary biophysical techniques including nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR), we show that raloxifene interacts specifically with the organic component or the organic/mineral composite, and not with hydroxyapatite. Structure-activity studies reveal that the basic side chain of raloxifene is an instrumental determinant in the interaction with bone. Thus, truncation of portions of the side chain reduces bone binding and also diminishes the increase in mechanical properties. Our results support a model wherein the piperidine interacts with bone matrix through electrostatic interactions with the piperidine nitrogen and through hydrophobic interactions (van der Waals) with the aliphatic groups in the side chain and the benzothiophene core. Furthermore, in silico prediction of the potential binding sites on the surface of collagen revealed the presence of a groove with sufficient space to accommodate raloxifene analogs. The hydroxyl groups on the benzothiophene nucleus, which are necessary for binding of SERMs to the estrogen receptor, are not required for binding to the bone surface, but mediate a more robust binding of the compound to the bone powder. In conclusion, we report herein a novel property of raloxifene analogs that allows them to interact with the bone tissue through potential contacts with the organic matrix and in particular collagen.

Original languageEnglish (US)
Pages (from-to)759-767
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume24
DOIs
StatePublished - 2016

Fingerprint

Bone Matrix
Bone
Bone and Bones
Selective Estrogen Receptor Modulators
Estrogen Receptors
Collagen
Organic minerals
Tissue
Mechanical properties
Fourier Transform Infrared Spectroscopy
Durapatite
Raloxifene Hydrochloride
Static Electricity
Hydrophobic and Hydrophilic Interactions
Hydroxyl Radical
Computer Simulation
Powders
Coulomb interactions
Minerals
Magnetic Resonance Spectroscopy

Keywords

  • Bone powder
  • Collagen
  • Raloxifene
  • SERM

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Bivi, N., Hu, H., Chavali, B., Chalmers, M. J., Reutter, C. T., Durst, G. L., ... Dodge, J. A. (2016). Structural features underlying raloxifene's biophysical interaction with bone matrix. Bioorganic and Medicinal Chemistry, 24, 759-767. https://doi.org/10.1016/j.bmc.2015.12.045

Structural features underlying raloxifene's biophysical interaction with bone matrix. / Bivi, Nicoletta; Hu, Haitao; Chavali, Balagopalakrishna; Chalmers, Michael J.; Reutter, Christopher T.; Durst, Gregory L.; Riley, Anna; Sato, Masahiko; Allen, Matthew; Burr, David; Dodge, Jeffrey A.

In: Bioorganic and Medicinal Chemistry, Vol. 24, 2016, p. 759-767.

Research output: Contribution to journalArticle

Bivi, N, Hu, H, Chavali, B, Chalmers, MJ, Reutter, CT, Durst, GL, Riley, A, Sato, M, Allen, M, Burr, D & Dodge, JA 2016, 'Structural features underlying raloxifene's biophysical interaction with bone matrix', Bioorganic and Medicinal Chemistry, vol. 24, pp. 759-767. https://doi.org/10.1016/j.bmc.2015.12.045
Bivi, Nicoletta ; Hu, Haitao ; Chavali, Balagopalakrishna ; Chalmers, Michael J. ; Reutter, Christopher T. ; Durst, Gregory L. ; Riley, Anna ; Sato, Masahiko ; Allen, Matthew ; Burr, David ; Dodge, Jeffrey A. / Structural features underlying raloxifene's biophysical interaction with bone matrix. In: Bioorganic and Medicinal Chemistry. 2016 ; Vol. 24. pp. 759-767.
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