Discovery of potential sclerostin inhibitors from plants with loop2 region of sclerostin inhibition by interacting with residues outside Pro-Asn-Ala-Ile-Gly motif

Yooin, Wipawadee; Saenjum, Chalermpong; Ruangsuriya, Jetsada; Jiranusornkul, Supat

doi:10.1080/07391102.2019.1599427

Cited by 10 publications

(5 citation statements)

References 43 publications

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“…30 They found nine small compounds with high predicted binding affinity using web resources for loop 2. Yooin et al 31 used computational molecular docking to identify probable herbal drugs that would target loop 2 and act as stimulators of bone growth. Their virtual screening trials discovered a collection of aryl-containing herbal medicines.…”

Section: Discussionmentioning

confidence: 99%

Identification of Repurposed FDA Drugs by Targeting Sclerostin via the Wnt Pathway for Alveolar Bone Formation

Yadalam,

Anegundi,

Ramadoss

et al. 2024

European Journal of General Dentistry

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Objective Natural wingless-related integration site (Wnt) pathway antagonist sclerostin (SOST) has attracted much attention because unusual bone illnesses characterized by the increased bone mass result from its absence of action. The Wnt ligand is prevented from attaching to the Frizzled family receptor when SOST is present. In the active destruction complex, -catenin is phosphorylated. -Catenin molecules do not enter the nucleus and are broken down by a proteasome. As a result, Wnt-responsive genes are not activated, which lowers bone formation and raises bone resorption. A humanized monoclonal antibody called romosozumab binds to and inhibits SOST with significant cardiac side effects. As a result, the current study's objective is to find and screen Food and Drug Administration (FDA) medications that target SOST. Materials and Methods SOST's structure was retrieved from Protein Data Bank (PDB) (ID: 6l6r). Pharmacophore modeling and molecular operating environment-based virtual testing of FDA-approved medicines. Using the Desmond program, docking and molecular dynamics simulations were performed. Results Our findings revealed medications with FDA approval (ZINC000253387843) Amphotericin B. The stability and receptor–ligand interactions are pretty substantial, as demonstrated by the findings of docking and Molecular dynamics simulations, which have a docking score of −7.3 k/mol and root mean square deviation stability at 40 nanoseconds, respectively. Conclusion The suggested pharmacological therapy shows promise since it uses the Wnt pathway to target the primary bone formation mechanism. However, additional prospective studies are required to apply the available data to clinical practice.

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Section: Discussionmentioning

confidence: 99%

Identification of Repurposed FDA Drugs by Targeting Sclerostin via the Wnt Pathway for Alveolar Bone Formation

Yadalam,

Anegundi,

Ramadoss

et al. 2024

European Journal of General Dentistry

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“…From our previous works, BA has demonstrated outstanding therapeutic effects to treat osteoporosis and promote bone regeneration. Based on the molecular docking results, BA demonstrates a high affinity toward the binding with the amino acid residues in loop 2 of Scl, indicating its potential inhibition against Scl. , Hence, BA is selected and formulated into a nanocomplex (BNP) to overcome its solubility issues. To explore its mechanism of action, the effect of BNP on Scl was investigated in MLO-Y4 cells.…”

Section: Discussionmentioning

confidence: 99%

“…In the past decade, natural products, especially flavonoids, have received increasing attention in the field of bone tissue engineering, e.g. , icariin has been well demonstrated with dose-dependent osteogenic potential by activation of bone morphogenetic protein 2 (BMP-2). , Interestingly, baicalin (BA), also a natural flavonoid, shows a high affinity toward Scl according to the molecular docking technology . Our previous works reported the great therapeutic potential of Radix scutellariae extracts abundant with BA to prevent disuse-induced osteoporosis. , Besides, BA induces osteogenic differentiation via the Wnt/β-catenin signaling pathway, inhibits osteoclast differentiation, and induces mature osteoclast apoptosis, which are critical events mediating the repair and regeneration of bones. , Hence, BA becomes a therapeutic candidate with great potential in modulating bone repair.…”

Section: Introductionmentioning

confidence: 99%

“…19,20 Interestingly, baicalin (BA), also a natural flavonoid, shows a high affinity toward Scl according to the molecular docking technology. 21 Our previous works reported the great therapeutic potential of Radix scutellariae extracts abundant with BA to prevent disuse-induced osteoporosis. 22,23 Besides, BA induces osteogenic differentiation via the Wnt/β-catenin signaling pathway, inhibits osteoclast differentiation, and induces mature osteoclast apoptosis, which are critical events mediating the repair and regeneration of bones.…”

Section: Introductionmentioning

confidence: 99%

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Baicalin Nanocomplexes with an In Situ-Forming Biomimetic Gel Implant for Repair of Calvarial Bone Defects via Localized Sclerostin Inhibition

Wang

Niu

et al. 2023

ACS Appl. Mater. Interfaces

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In situ-forming hydrogels are highly effective in covering complex and irregular tissue defects. Herein, a biomimetic gel implant (CS-GEL) consisting of methacrylated chondroitin sulfate and gelatin is obtained via visible light irradiation, which displays rapid gelation (∼30 s), suitable mechanical properties, and biological features to support osteoblast attachment and proliferation. Sclerostin is proven to be a viable target to promote osteogenesis. Hence, baicalin, a natural flavonoid with a high affinity to sclerostin, is selected as the therapeutic compound to achieve localized neutralization of sclerostin. To overcome its poor solubility and permeability, a baicalin nanocomplex (BNP) is synthesized using Solutol HS15, which is then dispersed in the CS-GEL to afford a nanocomposite delivery system, i.e., BNP-loaded gel (BNP@CS-GEL). In vitro, BNP significantly downregulated the level of sclerostin in MLO-Y4 osteocytes. In vivo, either CS-GEL or BNP@CS-GEL is proven to effectively promote osteogenesis and angiogenesis in a calvarial critical-sized bone defect rat model, with BNP@CS-GEL showing the best pro-healing effect. Specifically, the BNP@CS-GEL-treated group significantly downregulated the sclerostin level as compared to the sham group (p < 0.05). RANKL expression was also significantly suppressed by BNP in MLO-Y4 cells and BNP@CS-GEL in vivo. Collectively, our study offers a facile and viable gel platform in combination with nanoparticulated baicalin for the localized neutralization of sclerostin to promote bone regeneration and repair.

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“…At present, several potential sclerostin inhibitors screened by computer virtual screening have been reported, but the functional validation of animal and cell experiments has not been conducted. It includes a small molecular cluster 206 and a group of herbal compounds with an aromatic group, 207 targeting the loop 2 domain in sclerostin. A quinoxaline derivative targeting LRP5/6–sclerotin interaction 208 …”

Section: Anti‐osteoporosis Therapiesmentioning

confidence: 99%

Mechanistic advances in osteoporosis and anti‐osteoporosis therapies

Wang

Luo

Wang

et al. 2023

MedComm

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Osteoporosis is a type of bone loss disease characterized by a reduction in bone mass and microarchitectural deterioration of bone tissue. With the intensification of global aging, this disease is now regarded as one of the major public health problems that often leads to unbearable pain, risk of bone fractures, and even death, causing an enormous burden at both the human and socioeconomic layers. Classic anti‐osteoporosis pharmacological options include anti‐resorptive and anabolic agents, whose ability to improve bone mineral density and resist bone fracture is being gradually confirmed. However, long‐term or high‐frequency use of these drugs may bring some side effects and adverse reactions. Therefore, an increasing number of studies are devoted to finding new pathogenesis or potential therapeutic targets of osteoporosis, and it is of great importance to comprehensively recognize osteoporosis and develop viable and efficient therapeutic approaches. In this study, we systematically reviewed literatures and clinical evidences to both mechanistically and clinically demonstrate the state‐of‐art advances in osteoporosis. This work will endow readers with the mechanistical advances and clinical knowledge of osteoporosis and furthermore present the most updated anti‐osteoporosis therapies.

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Discovery of potential sclerostin inhibitors from plants with loop2 region of sclerostin inhibition by interacting with residues outside Pro-Asn-Ala-Ile-Gly motif

Cited by 10 publications

References 43 publications

Identification of Repurposed FDA Drugs by Targeting Sclerostin via the Wnt Pathway for Alveolar Bone Formation

Identification of Repurposed FDA Drugs by Targeting Sclerostin via the Wnt Pathway for Alveolar Bone Formation

Baicalin Nanocomplexes with an In Situ-Forming Biomimetic Gel Implant for Repair of Calvarial Bone Defects via Localized Sclerostin Inhibition

Mechanistic advances in osteoporosis and anti‐osteoporosis therapies

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