Predicting binding affinities of nitrogen-containing bisphosphonates on hydroxyapatite surface by molecular dynamics

Lin, Tzu-Jen

doi:10.1016/j.cplett.2018.12.008

Cited by 14 publications

(11 citation statements)

References 58 publications

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“…This is mainly due to the presence of nitrogenous functional groups on the R2 side chain [74,75]. The results from kinetic studies of the HA crystal growth showed that the ranking of the capability of binding to HA at neat surfaces among BPs is zoledronic acid > pamidronate > alendronate > ibandronate > risedronate > etidronate > clodronate [76]. BPs from different generations and their structural differences are illustrated in Table 2.…”

Section: Bisphosphonatementioning

confidence: 99%

Breast Cancer Bone Metastasis: A Narrative Review of Emerging Targeted Drug Delivery Systems

Shao

Varamini

2022

Cells

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Bone is one of the most common metastatic sites among breast cancer (BC) patients. Once bone metastasis is developed, patients’ survival and quality of life will be significantly declined. At present, there are limited therapeutic options for BC patients with bone metastasis. Different nanotechnology-based delivery systems have been developed aiming to specifically deliver the therapeutic agents to the bone. The conjugation of targeting agents to nanoparticles can enhance the selective delivery of various payloads to the metastatic bone lesion. The current review highlights promising and emerging advanced nanotechnologies designed for targeted delivery of anticancer therapeutics, contrast agents, photodynamic and photothermal materials to the bone to achieve the goal of treatment, diagnosis, and prevention of BC bone metastasis. A better understanding of various properties of these new therapeutic approaches may open up new landscapes in medicine towards improving the quality of life and overall survival of BC patients who experience bone metastasis.

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Section: Bisphosphonatementioning

confidence: 99%

Breast Cancer Bone Metastasis: A Narrative Review of Emerging Targeted Drug Delivery Systems

Shao

Varamini

2022

Cells

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“…Yet, very few computer modeling attempts are hitherto made to account for the structural disorder at the HA surface and its (potential) dependence on the pH of the surrounding aqueous medium. [50][51][52][53]70,71 Some progress toward a more accurate modeling of the biomolecular surface binding at HA was provided by Heinz and co-workers, 50−52 who introduced an HA surface model that partially accounts for structural disorder, while assuming that the phosphate speciation at the surface matches that of the surrounding aqueous solution at a given pH. 52 By employing the INTERFACE force field 52,70 and the HA surface preparation protocol according to ref 52 (see Sections 2 and 3), we present atomistic MD simulations utilizing variational enhanced sampling (VES) metadynamics 60 to examine the adsorption of Pser and citrate for variable pH values between 4.5 and 14.0 at the two (100) and (001) surfaces of the hexagonal HA modification 72 (reviewed in Section 2).…”

Section: Introductionmentioning

confidence: 99%

“…Given current limitations of a detailed experimental probing of the surface binding at atomic resolution, computer modeling by atomistic molecular dynamics (MD) simulations offers a rich source of structural information of the organic/inorganic interface, ,,− enabling the extraction of the precise binding sites (atoms of a given functional group), as well as the detailed surface-immobilized molecular conformationhereafter referred to as the binding mode of the molecule. Such simulations typically target a three-component system that involves one or several biomolecules in an aqueous solution in contact with a slab of HA.…”

Section: Introductionmentioning

confidence: 99%

“…A more fundamental problem with nearly all current DFT/AIMD/MD simulations, however, concerns the HA surface speciation of these models, where the prevailing approach is to cleave the stoichiometric HA crystal and preserve its periodicity, ,− ,,− which is tantamount to assuming that the simulated HA surface is present in a solution with pH > 14, i.e., far from physiological conditions. − Moreover, it is nowadays well established that all synthetic/biogenic nanometer-sized HA particles exhibit a core – shell organization, where an ordered core of “apatitic” Ca 2+ , PO 4 3– , and OH – ions is coated by a 1–2 nm thick surface layer of ACP, rich in acidic phosphate (HPO 4 2– ) moieties and water but essentially devoid of isolated (HA-type) hydroxyl groups, ,,− and often termed the “hydrated surface layer”. ,, Hence, biomolecules adsorbing at HA (“apatite”) nanoparticles interact with amorphous, rather than well-ordered, domains. As pointed out previously, ,, this property has strong bearings for a faithful computer modeling of biomolecule–HA interactions, as the adsorption de facto occurs at the surface layer of ACP, whose hydrated and disordered CaP environments are distinctly different from a perfect HA structure.…”

Section: Introductionmentioning

confidence: 99%

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Metadynamics Simulations of the pH-Dependent Adsorption of Phosphoserine and Citrate on Disordered Apatite Surfaces: What Interactions Govern the Molecular Binding?

Stevensson

Edén

2021

J. Phys. Chem. C

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Both citrate ions and proteins with phosphorylated side chains are believed to play central roles in bone mineralization. Using metadynamics simulations, we elucidated the pH-dependent surface binding of citrate and O-phospho-l-serine (Pser) at structurally disordered (100) and (001) surfaces of Ca hydroxyapatite (HA), the mother structure of bone mineral. The binding strength of Pser at the (100) surface increased concurrently with the pH value from 4.5 to 14.0 and remained consistently stronger than that at the (001) surface. In contrast, citrate revealed very similar adsorption affinities at both (100) and (001) surfaces throughout 7.4 ≤ pH ≤ 12.3, whereas adsorption at the (100) surface was favored at the lowest (4.5) and highest (14.0) pH values. The two most stable/probable binding modes of citrate involved either a simultaneous anchoring of all three COO– groups such that the molecule caps the HA surface or a “tilted” configuration stemming from the dual binding of the central and one terminal COO– moiety. The surface adsorption of Pser is dominated by its phosphate group, which participates in all significant binding modes, with the two most prominent ones featuring either a co-binding of the PO4 and COO– sites or a linear alignment of the molecule with the surface by the simultaneous anchoring of all three phosphate, carboxy, and amino groups. The latter constitutes the most stable binding mode at the (100) surface for pH = 7.4. We also introduced a straightforward analysis protocol based on Debye–Hückel energies, enabling the quantification of the relative contributions of each functional group of an adsorbed molecule, as well as its underlying interaction energies with the surface. Both the Pser and citrate adsorption occurred predominantly through electrostatic Ca2+–COO–/PO4 2– interactions, along with overall minor H-bond contributions, except for the Pser binding at the PO4-richer (001) HA surface for pH values between 7.4 and 12.3. We highlight the importance of excluding OH groups in the HA surface model to better mimic real nanocrystalline apatite particles and improve the accuracy of the adsorption modeling.

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“…The latter is crucial to bind HA and for the drug’s mechanism of action [ 26 , 27 ]. Indeed, due to their chemical attraction with metal cations, BPs strongly bind HA calcium phosphate crystals, inhibiting their accretion [ 28 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

A 3D Printed Composite Scaffold Loaded with Clodronate to Regenerate Osteoporotic Bone: In Vitro Characterization

Cometa¹,

Bonifacio

Tranquillo

et al. 2021

Polymers

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Additive manufacturing (AM) is changing our current approach to the clinical treatment of bone diseases, providing new opportunities to fabricate customized, complex 3D structures with bioactive materials. Among several AM techniques, the BioCell Printing is an advanced, integrated system for material manufacture, sterilization, direct cell seeding and growth, which allows for the production of high-resolution micro-architectures. This work proposes the use of the BioCell Printing to fabricate polymer-based scaffolds reinforced with ceramics and loaded with bisphosphonates for the treatment of osteoporotic bone fractures. In particular, biodegradable poly(ε-caprolactone) was blended with hydroxyapatite particles and clodronate, a bisphosphonate with known efficacy against several bone diseases. The scaffolds’ morphology was investigated by means of Scanning Electron Microscopy (SEM) and micro-Computed Tomography (micro-CT) while Energy Dispersive X-ray Spectroscopy (EDX) and X-ray Photoelectron Spectroscopy (XPS) revealed the scaffolds’ elemental composition. A thermal characterization of the composites was accomplished by Thermogravimetric analyses (TGA). The mechanical performance of printed scaffolds was investigated under static compression and compared against that of native human bone. The designed 3D scaffolds promoted the attachment and proliferation of human MSCs. In addition, the presence of clodronate supported cell differentiation, as demonstrated by the normalized alkaline phosphatase activity. The obtained results show that the BioCell Printing can easily be employed to generate 3D constructs with pre-defined internal/external shapes capable of acting as a temporary physical template for regeneration of cancellous bone tissues.

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Predicting binding affinities of nitrogen-containing bisphosphonates on hydroxyapatite surface by molecular dynamics

Cited by 14 publications

References 58 publications

Breast Cancer Bone Metastasis: A Narrative Review of Emerging Targeted Drug Delivery Systems

Breast Cancer Bone Metastasis: A Narrative Review of Emerging Targeted Drug Delivery Systems

Metadynamics Simulations of the pH-Dependent Adsorption of Phosphoserine and Citrate on Disordered Apatite Surfaces: What Interactions Govern the Molecular Binding?

A 3D Printed Composite Scaffold Loaded with Clodronate to Regenerate Osteoporotic Bone: In Vitro Characterization

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