title: Structural features underlying raloxifene's biophysical interaction with bone matrix.
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.
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, United States.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Bivi
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, United States.
authors.forename: Haitao
authors.initials: H
authors.lastname: Hu
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, United States.
authors.forename: Balagopalakrishna
authors.initials: B
authors.lastname: Chavali
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chalmers
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, United States.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Reutter
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, United States.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Durst
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Riley
authors.affiliation: Indiana University Purdue University Indianapolis, Indianapolis, IN, United States.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sato
authors.affiliation: Indiana University Purdue University Indianapolis, Indianapolis, IN, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Allen
authors.affiliation: Indiana University Purdue University Indianapolis, Indianapolis, IN, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Burr
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN, United States.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Dodge
mesh_terms: D000818:Animals; D001857:Bone Matrix / Q000187:drug effects* / Q000378:metabolism; D003094:Collagen / Q000737:chemistry / Q000378:metabolism*; D004285:Dogs; D017886:Durapatite / Q000737:chemistry; D005269:Femur / Q000187:drug effects* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D010880:Piperidines / Q000737:chemistry; D011107:Polylysine / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020849:Raloxifene Hydrochloride / Q000378:metabolism / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry
chemical_list: D010880:Piperidines; D011960:Receptors, Estrogen; D013876:Thiophenes; D011107:Polylysine; D020849:Raloxifene Hydrochloride; D003094:Collagen; D017886:Durapatite
keywords: Bone powder; Collagen; Raloxifene; SERM