In Vitro andIn Vivo induction of bone formation using a recombinant adenoviral vector carrying the human BMP-2 gene

Oral tissue regeneration has received growing attention for improving the quality of life of patients. Regeneration of oral tissues such as alveolar bone and widely defected bone has been extensively investigated, including regenerative treatment of oral tissues using therapeutic cells and growth factors. Additionally, small-molecule drugs that promote bone formation have been identified and tested as new regenerative treatment. However, treatments need to progress to realize successful regeneration of oral functions. In this review, we describe recent progress in development of regenerative treatment of oral tissues. In particular, we focus on cyclodextrin (CD)-based pharmaceutics and polyelectrolyte complexation of growth factors to enhance their solubility, stability, and bioactivity. CDs can encapsulate hydrophobic small-molecule drugs into their cavities, resulting in inclusion complexes. The inclusion complexation of osteoinductive small-molecule drugs improves solubility of the drugs in aqueous solutions and increases in vitro osteogenic differentiation efficiency. Additionally, various anionic polymers such as heparin and its mimetic polymers have been developed to improve stability and bioactivity of growth factors. These polymers protect growth factors from deactivation and degradation by complex formation through electrostatic interaction, leading to potentiation of bone formation ability. These approaches using an inclusion complex and polyelectrolyte complexes have great potential in the regeneration of oral tissues.

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Computational prediction of small molecules with predicted binding to FGFR3 and testing biological effects in bone cells

Experimental Biology and Medicine ◽

10.1177/15353702211002181 ◽

2021 ◽

pp. 153537022110021

Author(s):

Subburaman Mohan ◽

Karthikeyan Muthusamy ◽

Selvaraman Nagamani ◽

Chandrasekhar Kesavan

Keyword(s):

Bone Formation ◽

Small Molecules ◽

Density Functional ◽

Absorption Rate ◽

Oral Absorption ◽

Bone Cells ◽

Biological Effects ◽

Dynamics Simulation ◽

Molecular Stability

Activating anabolic receptor-mediated signaling is essential for stimulating new bone formation and for promoting bone healing in humans. Fibroblast growth factor receptor (FGFR) 3 is reported to be an important positive regulator of osteogenesis. Presently, recombinant proteins are used to stimulate FGFR3 function but have limitations for therapy due to expense and stability. Therefore, there is a need for identification of novel small molecules binding to FGFR3 that promote biological function. In silico molecular docking and high-throughput virtual screening on zinc database identified seven compounds predicted to bind to an active site within the βCʹ-βE loop, specific to FGFR3. All seven compounds fall within an acceptable range of ADME/T properties. Four compounds showed a 30–65% oral absorption rate. Density functional theory analysis revealed a high HOMO-LUMO gap, reflecting high molecular stability for compounds 14977614 and 13509082. Five compounds exhibited mutagenicity, while the other three compounds presented irritability. Computational mutagenesis predicted that mutating G322 affected compound binding to FGFR3. Molecular dynamics simulation revealed compound 14977614 is stable in binding to FGFR3. Furthermore, compound 14977614, with an oral absorption rate of 60% and high molecular stability, produced significant increases in both proliferation and differentiation of bone marrow stromal cells in vitro. Anti-FGFR3 treatment completely blocked the stimulatory effect of 14977614 on BMSC proliferation. Ex vivo treatment of mouse calvaria in organ culture for seven days with 14977614 increased mineralization and expression levels of bone formation markers. In conclusion, computational analyses identified seven compounds that bind to the FGFR3, and in vitro studies showed that compound 14977614 exerts significant biological effects on osteogenic cells.

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